Статті в журналах з теми "KIT tyrosine kinase"
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1
Heinrich, Michael C., Diana J. Griffith, Brian J. Druker, Cecily L. Wait, Kristen A. Ott, and Amy J. Zigler. "Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor." Blood 96, no. 3 (August 1, 2000): 925–32. http://dx.doi.org/10.1182/blood.v96.3.925.
Повний текст джерелаАнотація:
Abstract STI 571 (formerly known as CGP 57148B) is a known inhibitor of the c-abl, bcr-abl, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinases. This compound is being evaluated in clinical trials for the treatment of chronic myelogenous leukemia. We sought to extend the activity profile of STI 571 by testing its ability to inhibit the tyrosine kinase activity of c-kit, a receptor structurally similar to PDGFR. We treated a c-kit expressing a human myeloid leukemia cell line, M-07e, with STI 571 before stimulation with Steel factor (SLF). STI 571 inhibited c-kit autophosphorylation, activation of mitogen-activated protein (MAP) kinase, and activation of Akt without altering total protein levels of c-kit, MAP kinase, or Akt. The concentration that produced 50% inhibition for these effects was approximately 100 nmol/L. STI 571 also significantly decreased SLF-dependent growth of M-07e cells in a dose-dependent manner and blocked the antiapoptotic activity of SLF. In contrast, the compound had no effect on MAP kinase activation or cellular proliferation in response to granulocyte-macrophage colony-stimulating factor. We also tested the activity of STI 571 in a human mast cell leukemia cell line (HMC-1), which has an activated mutant form of c-kit. STI 571 had a more potent inhibitory effect on the kinase activity of this mutant receptor than it did on ligand-dependent activation of the wild-type receptor. These findings show that STI 571 selectively inhibits c-kit tyrosine kinase activity and downstream activation of target proteins involved in cellular proliferation and survival. This compound may be useful in treating cancers associated with increased c-kit kinase activity.
2
Heinrich, Michael C., Diana J. Griffith, Brian J. Druker, Cecily L. Wait, Kristen A. Ott, and Amy J. Zigler. "Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor." Blood 96, no. 3 (August 1, 2000): 925–32. http://dx.doi.org/10.1182/blood.v96.3.925.015k50_925_932.
Повний текст джерелаАнотація:
STI 571 (formerly known as CGP 57148B) is a known inhibitor of the c-abl, bcr-abl, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinases. This compound is being evaluated in clinical trials for the treatment of chronic myelogenous leukemia. We sought to extend the activity profile of STI 571 by testing its ability to inhibit the tyrosine kinase activity of c-kit, a receptor structurally similar to PDGFR. We treated a c-kit expressing a human myeloid leukemia cell line, M-07e, with STI 571 before stimulation with Steel factor (SLF). STI 571 inhibited c-kit autophosphorylation, activation of mitogen-activated protein (MAP) kinase, and activation of Akt without altering total protein levels of c-kit, MAP kinase, or Akt. The concentration that produced 50% inhibition for these effects was approximately 100 nmol/L. STI 571 also significantly decreased SLF-dependent growth of M-07e cells in a dose-dependent manner and blocked the antiapoptotic activity of SLF. In contrast, the compound had no effect on MAP kinase activation or cellular proliferation in response to granulocyte-macrophage colony-stimulating factor. We also tested the activity of STI 571 in a human mast cell leukemia cell line (HMC-1), which has an activated mutant form of c-kit. STI 571 had a more potent inhibitory effect on the kinase activity of this mutant receptor than it did on ligand-dependent activation of the wild-type receptor. These findings show that STI 571 selectively inhibits c-kit tyrosine kinase activity and downstream activation of target proteins involved in cellular proliferation and survival. This compound may be useful in treating cancers associated with increased c-kit kinase activity.
3
Ledoux, Julie, and Luba Tchertanov. "Does Generic Cyclic Kinase Insert Domain of Receptor Tyrosine Kinase KIT Clone Its Native Homologue?" International Journal of Molecular Sciences 23, no. 21 (October 25, 2022): 12898. http://dx.doi.org/10.3390/ijms232112898.
Повний текст джерелаАнотація:
Receptor tyrosine kinases (RTKs) are modular membrane proteins possessing both well-folded and disordered domains acting together in ligand-induced activation and regulation of post-transduction processes that tightly couple extracellular and cytoplasmic events. They ensure the fine-turning control of signal transmission by signal transduction. Deregulation of RTK KIT, including overexpression and gain of function mutations, has been detected in several human cancers. In this paper, we analysed by in silico techniques the Kinase Insert Domain (KID), a key platform of KIT transduction processes, as a generic macrocycle (KIDGC), a cleaved isolated polypeptide (KIDC), and a natively fused TKD domain (KIDD). We assumed that these KID species have similar structural and dynamic characteristics indicating the intrinsically disordered nature of this domain. This finding means that both polypeptides, cyclic KIDGC and linear KIDC, are valid models of KID integrated into the RTK KIT and will be helpful for further computational and empirical studies of post-transduction KIT events.
4
Marmigère, Frédéric, Frédérique Scamps, and Jean Valmier. "Le récepteur tyrosine kinase c-Kit." médecine/sciences 24, no. 5 (May 2008): 464–66. http://dx.doi.org/10.1051/medsci/2008245464.
Повний текст джерела
5
Bandi, Srinivasa Rao, Christian Brandts, Marion Rensinghoff, Rebekka Grundler, Lara Tickenbrock, Gabriele Köhler, Justus Duyster, et al. "E3 ligase–defective Cbl mutants lead to a generalized mastocytosis and myeloproliferative disease." Blood 114, no. 19 (November 5, 2009): 4197–208. http://dx.doi.org/10.1182/blood-2008-12-190934.
Повний текст джерелаАнотація:
Abstract Somatic mutations of Kit have been found in leukemias and gastrointestinal stromal tumors. The proto-oncogene c-Cbl negatively regulates Kit and Flt3 by its E3 ligase activity and acts as a scaffold. We recently identified the first c-Cbl mutation in human disease in an acute myeloid leukemia patient, called Cbl-R420Q. Here we analyzed the role of Cbl mutants on Kit-mediated transformation. Coexpression of Cbl-R420Q or Cbl-70Z with Kit induced cytokine-independent proliferation, survival, and clonogenic growth. Primary murine bone marrow retrovirally transduced with c-Cbl mutants and transplanted into mice led to a generalized mastocytosis, a myeloproliferative disease, and myeloid leukemia. Overexpression of these Cbl mutants inhibited stem cell factor (SCF)–induced ubiquitination and internalization of Kit. Both Cbl mutants enhanced the basal activation of Akt and prolonged the ligand-dependent activation. Importantly, transformation was observed also with kinase-dead forms of Kit and Flt3 in the presence of Cbl-70Z, but not in the absence of Kit or Flt3, suggesting a mechanism dependent on receptor tyrosine kinases, but independent of their kinase activity. Instead, transformation depends on the Src family kinase Fyn, as c-Cbl coimmunoprecipitated with Fyn and inhibition abolished transformation. These findings may explain primary resistance to tyrosine kinase inhibitors targeted at receptor tyrosine kinases.
6
Kinashi, T., JA Escobedo, LT Williams, K. Takatsu, and TA Springer. "Receptor tyrosine kinase stimulates cell-matrix adhesion by phosphatidylinositol 3 kinase and phospholipase C-gamma 1 pathways." Blood 86, no. 6 (September 15, 1995): 2086–90. http://dx.doi.org/10.1182/blood.v86.6.2086.bloodjournal8662086.
Повний текст джерелаАнотація:
Receptor tyrosine kinases are known to be important in growth and differentiation. We have recently found that c-kit, the tyrosine kinase receptor for steel factor, also regulates cell-matrix adhesion. Because Steel factor helps regulate cell migration and localization, this may be an important biologic function. Integrin adhesiveness is regulated within minutes by c-kit. The signaling pathways for tyrosine kinase stimulation of integrin adhesiveness and their relation to pathways that regulate growth and differentiation over much longer time periods remain uncharacterized. We have studied the effector pathways by which receptor tyrosine kinases regulate cell-matrix adhesion using wild-type and mutant forms of the platelet-derived growth factor (PDGF) receptor, which is closely related to c-kit. The PDGF receptor expressed in mast cells is as potent as c-kit in stimulating adhesion to fibronectin. We show that induction of adhesion is regulated through two independent pathways of phosphatidylinositol 3 kinase (PI3K) and phospholipase C- gamma 1 (PLC gamma)-protein kinase C by elimination of autophosphorylation sites required for activation of PI3K and PLC gamma or in combination with downregulation of protein kinase C or wortmannin. By contrast, a receptor mutated in both the PI3K and PLC gamma association sites can still stimulate mast cell growth, indicating a crucial role of these effector molecules in regulating adhesion rather than cell growth.
7
Sun, Jianmin, Malin Pedersen, and Lars Rönnstrand. "The D816V Mutation of C-Kit Circumvents a Requirement for Src Family Kinases in C-Kit Mediated Signal Tranduction and Transformation." Blood 112, no. 11 (November 16, 2008): 2849. http://dx.doi.org/10.1182/blood.v112.11.2849.2849.
Повний текст джерелаАнотація:
Abstract The receptor tyrosine kinase c-Kit plays a critical role in hematopoiesis and gain-of-function mutations of the receptor are frequently seen in several malignancies, including acute myeloid leukemia (AML), mastocytoma and sinonasal NK/T cell lymphomas. The most common mutation of c-Kit in these disorders is a substitution of the aspartic acid residue in position 816 to a valine (D816V), leading to constitutive activation of the receptor. In this study we aimed to investigate the role of Src family kinases in c-Kit/D816V signaling. Src family kinases are necessary for the phosphorylation of wild-type c-Kit as well as for activation of downstream signaling pathways including receptor ubiquitination and the Ras/MEK/Erk pathway. Tyrosine 568 of c-Kit, that is important for Src activation by wild-type c-Kit, was mutated to phenylalanine in both wild-type c-Kit and c-Kit/D816V and stably transfected into the hematopoietic cell line Ba/F3. Our data demonstrate that, unlike wild-type c-Kit, the phosphorylation of c-Kit/D816V is not dependent on Src family kinases. In addition we found that neither receptor ubiquitination nor Erk activation by c-Kit/D816V required activation of Src family kinases. In vitro kinase assay using synthetic peptides revealed that c-Kit/D816V had an altered substrate specificity resembling Src and Abl tyrosine kinases. The serine/threonine kinases Akt and Erk play important roles in cell survival and proliferation mediated by receptor tyrosine kinases. We could show constitutive activation of both PI3-kinase pathway and Erk in Ba/F3 cells expressing c-Kit/D816V, although ligand stimulation induced even stronger activation. We further present evidence that, in contrast to wild-type c-Kit, Src family kinases are dispensible for c-Kit/D816V cell survival. Taken together, we demonstrate that the signal transduction pathways mediated by c-Kit/D816V are markedly different from those activated by wild-type c-Kit and that altered substrate substrate specificity of c-Kit circumvents a need for Src family kinases in signaling of growth and survival, thereby contributing to the transforming potential of c-Kit/D816V.
8
Pan, Jingxuan, Hagop Kantarjian, Jorge Cortes, Francis Giles, and Srdan Verstovsek. "Effect of Tyrosine Kinase Inhibitor INNO-406 on Human Mast Cells Bearing Mutated c-KIT Tyrosine Kinase." Blood 108, no. 11 (November 16, 2006): 4890. http://dx.doi.org/10.1182/blood.v108.11.4890.4890.
Повний текст джерелаАнотація:
Abstract Systemic mastocytosis (SM) is characterized by a clonal accumulation of mast cells (MC) in bone marrow and other tissues. Malignant MC have abnormal spindle shape, express aberrant surface markers, and carry, in most cases, a mutation involving codon 816 of the c-KIT gene (D816V). This mutation results in a constitutively activated c-kit receptor associated tyrosine kinase and is responsible for disease progression. Agents that affect mutated c-kit may have clinical benefit in SM, but there is none clinically available. INNO-406 is a novel multi-targeted tyrosine kinase inhibitor, previously shown to inhibit the growth of cells expressing c-kit by inhibiting its phosphorylation (Kimura, Blood, 106:3948–54, 2005). We investigated the effects of INNO-406 on mast cells with mutated c-KIT, and compared it to that of imatinib mesylate, tyrosine kinase inhibitor effective against selected c-KIT mutants. HMC-1560 cells carrying juxtamembrane domain c-KIT mutation in codon 560, and HMC-1560, 816 cells carrying both codon 560 mutation and tyrosine kinase domain c-KIT mutation in codon 816, were exposed to increasing concentrations (0.02 to 5 μM) of INNO-406 or imatinib in 72-hour cell proliferation assay. Both INNO-406 and imatinib effectively inhibited the growth of HMC-1560 cells, with IC50 of 45 and 75nM, respectively. Neither drug was effective against HMC-1560, 816 cells at the doses tested. INNO-406 effectively induced apoptosis in HMC-1560, but not in HMC-1560, 816 cells, as judged by the Annexin V flow cytometry test and by PARP specific cleavage seen on western blotting. In addition, INNO-406 was effective in inhibiting phosphorylation of c-kit in HMC-1560 cells in nM range. Our results suggest similar potency of INNO-406 and imatinib in mast cells with mutated codon 560 (found in gastrointestinal stromal tumor), but no activity against cells with mutated codon 816 c-KIT (found in SM).
9
Kornbluth, S., K. E. Paulson, and H. Hanafusa. "Novel tyrosine kinase identified by phosphotyrosine antibody screening of cDNA libraries." Molecular and Cellular Biology 8, no. 12 (December 1988): 5541–44. http://dx.doi.org/10.1128/mcb.8.12.5541-5544.1988.
Повний текст джерелаАнотація:
In an attempt to clone protein tyrosine kinases, antiphosphotyrosine antibodies were used to screen lambda gt11 cDNA expression libraries. By this method, a 2.5-kilobase cDNA encoding a novel tyrosine kinase was isolated from a mouse liver cDNA library. This new gene is most closely related to the receptor tyrosine kinases ret, fms, and kit.
10
Kornbluth, S., K. E. Paulson, and H. Hanafusa. "Novel tyrosine kinase identified by phosphotyrosine antibody screening of cDNA libraries." Molecular and Cellular Biology 8, no. 12 (December 1988): 5541–44. http://dx.doi.org/10.1128/mcb.8.12.5541.
Повний текст джерелаАнотація:
In an attempt to clone protein tyrosine kinases, antiphosphotyrosine antibodies were used to screen lambda gt11 cDNA expression libraries. By this method, a 2.5-kilobase cDNA encoding a novel tyrosine kinase was isolated from a mouse liver cDNA library. This new gene is most closely related to the receptor tyrosine kinases ret, fms, and kit.
11
Masson, Kristina, Elke Heiss, Hamid Band, and Lars Rönnstrand. "Direct binding of Cbl to Tyr568 and Tyr936 of the stem cell factor receptor/c-Kit is required for ligand-induced ubiquitination, internalization and degradation." Biochemical Journal 399, no. 1 (September 13, 2006): 59–67. http://dx.doi.org/10.1042/bj20060464.
Повний текст джерелаАнотація:
The ubiquitin E3 ligase Cbl has been shown to negatively regulate tyrosine kinase receptors, including the stem cell factor receptor/c-Kit. Impaired recruitment of Cbl to c-Kit results in a deregulated positive signalling that eventually can contribute to carcinogenesis. Here, we present results showing that Cbl is activated by the SFKs (Src family kinases) and recruited to c-Kit in order to trigger receptor ubiquitination. We demonstrate that phosphorylated Tyr568 and Tyr936 in c-Kit are involved in direct binding and activation of Cbl and that binding of the TKB domain (tyrosine kinase binding domain) of Cbl to c-Kit is specified by the presence of an isoleucine or leucine residue in position +3 to the phosphorylated tyrosine residue on c-Kit. Apart from the direct association between Cbl and c-Kit, we show that phosphorylation of Cbl by SFK members is required for activation of Cbl to occur. Moreover, we demonstrate that Cbl mediates monoubiquitination of c-Kit and that the receptor is subsequently targeted for lysosomal degradation. Taken together, our findings reveal novel insights into the mechanisms by which Cbl negatively regulates c-Kit-mediated signalling.
12
Masson, Kristina, Elke Heiss, and Lars Ronnstrand. "Negative Regulation of c-Kit Is Dependent on Direct Binding of Cbl to Tyrosines 568 and 936." Blood 106, no. 11 (November 16, 2005): 2288. http://dx.doi.org/10.1182/blood.v106.11.2288.2288.
Повний текст джерелаАнотація:
Abstract C-Kit belongs to the family of type III receptor tyrosine kinases and is mainly expressed in hematopoietic precursor cells. Binding of stem cell factor (Kit ligand) leads to receptor dimerization, activation of intrinsic tyrosine kinase activity and cross-autophosphorylation of receptor tyrosine residues which provide specific docking sites for molecules that transduce the signal further downstream. Signaling through c-Kit results in several different cellular responses, most of which are directly involved in growth control and survival. Negative regulation of the receptor activity is therefore of much importance concerning pathogenic processes such as tumorigenesis in which activated c-Kit often plays a role. Here we present data showing that the ubiquitin E3 ligase Cbl must be activated by the Src family kinases and recruited to c-Kit in order to trigger receptor degradation. We demonstrate that the autophosphorylation sites Y568 and Y936 in c-Kit, previously reported to be binding sites for APS, Src or Grb2, respectively, are involved in Cbl recruitment and activation, possibly in a direct manner. I571 and L939 of c-Kit hereby determine the specificity for binding the N-terminal tyrosine kinase binding domain of Cbl. We show that activation of Cbl by Src family kinase members on one hand and direct or indirect recruitment of active Cbl to the pY568/I571 and pY936/L939 motifs of c-Kit on the other, are separable events and are both necessary for Cbl-mediated c-Kit degradation. Consistently, both the Y568/570F double mutant lacking Src kinase activity and the I571A/L939A double mutant lacking Cbl-specific interaction sites fail to ubiquitinate and degrade c-Kit upon ligand stimulation in stably transfected PAE and Ba/F3 cells. Thus, we could reveal novel aspects of the dynamic process of docking and activating signaling molecules at receptor phosphotyrosines that negatively regulate c-Kit-mediated responses. Moreover, we demonstrate that Cbl mediates monoubiquitination of c-Kit and that the receptor subsequently is targeted for lysosomal degradation. Taken together, our findings reveal novel insights on how c-Kit -mediated signal transduction is negatively regulated by Cbl.
13
DeBERRY, Candy, Sherry MOU, and Diana LINNEKIN. "Stat1 associates with c-kit and is activated in response to stem cell factor." Biochemical Journal 327, no. 1 (October 1, 1997): 73–80. http://dx.doi.org/10.1042/bj3270073.
Повний текст джерелаАнотація:
Interaction of stem cell factor (SCF), a haematopoietic growth factor, with the receptor tyrosine kinase c-kit leads to autophosphorylation of c-kit as well as tyrosine phosphorylation of various substrates. Little is known about the role of the JAK/STAT pathway in signal transduction via receptor tyrosine kinases, although this pathway has been well characterized in cytokine receptor signal transduction. We recently found that the Janus kinase Jak2 associates with c-kit and that SCF induces rapid and transient phosphorylation of Jak2. Here we present evidence that SCF activates the transcription factor Stat1. Phosphorylated c-kit co-immunoprecipitates with Stat1 within 1 min of SCF stimulation of the human cell line MO7e. Co-precipitation experiments using glutathione S-transferase fusion proteins indicate that association with c-kit is mediated by the Stat1 SH2 domain. Stat1 is rapidly tyrosine-phosphorylated in response to SCF in MO7e cells, the murine cell line FDCP-1 and normal progenitor cells. SCF-induced phosphorylation of Jak2 and Stat1 was also observed in murine 3T3 fibroblasts stably transfected with full-length human c-kit receptor. Furthermore c-kit directly phosphorylates Stat1 fusion proteins in in vitro kinase assays. Electrophoretic mobility-shift assays with nuclear extracts from SCF-stimulated cell lines and normal progenitor cells indicate that activated Stat1 binds the m67 oligonucleotide, a high-affinity SIE promoter sequence. These results demonstrate that Stat1 is activated in response to SCF, and suggest that Stat1 is a component of the SCF signal-transduction pathway.
14
Koltai, Zsófia, Bernadett Szabó, Judit Jakus, and Péter Vajdovich. "Tyrosine kinase expression analyses in canine mammary gland tumours – A pilot study." Acta Veterinaria Hungarica 66, no. 2 (June 2018): 294–308. http://dx.doi.org/10.1556/004.2018.027.
Повний текст джерелаАнотація:
Messenger RNA levels of oncogenic tyrosine kinases were determined in canine mammary tumours using real-time RT-PCR. The following tyrosine kinases and vascular endothelial growth factors (VEGF) were examined in malignant and healthy mammary tissues of 13 dogs: VEGFR1, VEGFR2, EGFR, ErbB2, PDGFR1, c-KIT and c-MET. Expression levels of all these factors were significantly higher in tumour samples than in normal mammary tissues taken from the same animal. Higher grading was associated with higher VEGFR1 levels. Grade III tumours showed significantly higher VEGF, c-MET and c-KIT mRNA expression, while Grade I tumours with lower malignancy showed significantly higher PDGFR1 and EGFR expression than tumours classified as Grade II or III. The increased presence of VEGF, VEGFR1, c-KIT and c-MET is a negative prognostic factor as these signal transduction molecules contribute to increased tumour malignancy. The presented data provide evidence, for the first time, for the existence of a complex overexpression and dysregulation of VEGF and several oncogenic tyrosine kinases such as VEGR1, PDGFR1, c-KIT and c-MET in canine mammary tumours. Therefore, canine mammary tumours may be potential targets for tyrosine kinase inhibitor therapy.
15
Rottapel, R., M. Reedijk, D. E. Williams, S. D. Lyman, D. M. Anderson, T. Pawson, and A. Bernstein. "The Steel/W transduction pathway: kit autophosphorylation and its association with a unique subset of cytoplasmic signaling proteins is induced by the Steel factor." Molecular and Cellular Biology 11, no. 6 (June 1991): 3043–51. http://dx.doi.org/10.1128/mcb.11.6.3043-3051.1991.
Повний текст джерелаАнотація:
The W/c-kit and Steel loci respectively encode a receptor tyrosine kinase (Kit) and its extracellular ligand, Steel factor, which are essential for the development of hematopoietic, melanocyte, and germ cell lineages in the mouse. To determine the biochemical basis of the Steel/W developmental pathway, we have investigated the response of the Kit tyrosine kinase and several potential cytoplasmic targets to stimulation with Steel in mast cells derived from normal and mutant W mice. In normal mast cells, Steel induces Kit to autophosphorylate on tyrosine and bind to phosphatidylinositol 3'-kinase (PI3K) and phospholipase C-gamma 1 but not detectably to Ras GTPase-activating protein. Additionally, we present evidence that Kit tyrosine phosphorylation acts as a switch to promote complex formation with PI3K. In mast cells from mice homozygous for the W42 mutant allele, Kit is not tyrosine phosphorylated and fails to bind PI3K following Steel stimulation. In contrast, in the transformed mast cell line P815, Kit is constitutively phosphorylated and binds to PI3K in the absence of ligand. These results suggest that Kit autophosphorylation and its physical association with a unique subset of cytoplasmic signaling proteins are critical for mammalian development.
16
Rottapel, R., M. Reedijk, D. E. Williams, S. D. Lyman, D. M. Anderson, T. Pawson, and A. Bernstein. "The Steel/W transduction pathway: kit autophosphorylation and its association with a unique subset of cytoplasmic signaling proteins is induced by the Steel factor." Molecular and Cellular Biology 11, no. 6 (June 1991): 3043–51. http://dx.doi.org/10.1128/mcb.11.6.3043.
Повний текст джерелаАнотація:
The W/c-kit and Steel loci respectively encode a receptor tyrosine kinase (Kit) and its extracellular ligand, Steel factor, which are essential for the development of hematopoietic, melanocyte, and germ cell lineages in the mouse. To determine the biochemical basis of the Steel/W developmental pathway, we have investigated the response of the Kit tyrosine kinase and several potential cytoplasmic targets to stimulation with Steel in mast cells derived from normal and mutant W mice. In normal mast cells, Steel induces Kit to autophosphorylate on tyrosine and bind to phosphatidylinositol 3'-kinase (PI3K) and phospholipase C-gamma 1 but not detectably to Ras GTPase-activating protein. Additionally, we present evidence that Kit tyrosine phosphorylation acts as a switch to promote complex formation with PI3K. In mast cells from mice homozygous for the W42 mutant allele, Kit is not tyrosine phosphorylated and fails to bind PI3K following Steel stimulation. In contrast, in the transformed mast cell line P815, Kit is constitutively phosphorylated and binds to PI3K in the absence of ligand. These results suggest that Kit autophosphorylation and its physical association with a unique subset of cytoplasmic signaling proteins are critical for mammalian development.
17
Tsujimura, T., T. Furitsu, M. Morimoto, K. Isozaki, S. Nomura, Y. Matsuzawa, Y. Kitamura, and Y. Kanakura. "Ligand-independent activation of c-kit receptor tyrosine kinase in a murine mastocytoma cell line P-815 generated by a point mutation." Blood 83, no. 9 (May 1, 1994): 2619–26. http://dx.doi.org/10.1182/blood.v83.9.2619.2619.
Повний текст джерелаАнотація:
Abstract The c-kit proto-oncogene encodes a receptor tyrosine kinase that is known to play a crucial role in hematopoiesis, especially in mast cell growth and differentiation. Although a number of dominant loss-of- function mutations of c-kit gene have been well characterized in mice, rats, and humans, little is known about the c-kit mutations contributing to ligand-independent activation of the c-kit receptor tyrosine kinase (KIT). In a murine mastocytoma cell line, P-815, KIT has been found to be constitutively phosphorylated on tyrosine and activated in a ligand-independent manner. Sequencing of the whole coding region of c-kit cDNA showed that c-kit cDNA of P-815 cells carries a point mutation in codon 814, resulting in amino acid substitution of Tyr for Asp. Murine wild-type c-kit cDNA and mutant- type c-kit cDNA encoding Tyr in codon 814 were expressed in cells of a human embryonic kidney cell line, 293T. In the transfected cells, mutant-form KITTyr814 was strikingly phosphorylated on tyrosine and activated in immune complex kinase reaction regardless of stimulation with a ligand for KIT (stem cell factor), whereas tyrosine phosphorylation and activation was barely detectable in wild-form KIT. The data presented here provide evidence for a novel activating mutation of c-kit gene that might be involved in neoplastic growth or oncogenesis of some cell types, including mast cells.
18
Tsujimura, T., T. Furitsu, M. Morimoto, K. Isozaki, S. Nomura, Y. Matsuzawa, Y. Kitamura, and Y. Kanakura. "Ligand-independent activation of c-kit receptor tyrosine kinase in a murine mastocytoma cell line P-815 generated by a point mutation." Blood 83, no. 9 (May 1, 1994): 2619–26. http://dx.doi.org/10.1182/blood.v83.9.2619.bloodjournal8392619.
Повний текст джерелаАнотація:
The c-kit proto-oncogene encodes a receptor tyrosine kinase that is known to play a crucial role in hematopoiesis, especially in mast cell growth and differentiation. Although a number of dominant loss-of- function mutations of c-kit gene have been well characterized in mice, rats, and humans, little is known about the c-kit mutations contributing to ligand-independent activation of the c-kit receptor tyrosine kinase (KIT). In a murine mastocytoma cell line, P-815, KIT has been found to be constitutively phosphorylated on tyrosine and activated in a ligand-independent manner. Sequencing of the whole coding region of c-kit cDNA showed that c-kit cDNA of P-815 cells carries a point mutation in codon 814, resulting in amino acid substitution of Tyr for Asp. Murine wild-type c-kit cDNA and mutant- type c-kit cDNA encoding Tyr in codon 814 were expressed in cells of a human embryonic kidney cell line, 293T. In the transfected cells, mutant-form KITTyr814 was strikingly phosphorylated on tyrosine and activated in immune complex kinase reaction regardless of stimulation with a ligand for KIT (stem cell factor), whereas tyrosine phosphorylation and activation was barely detectable in wild-form KIT. The data presented here provide evidence for a novel activating mutation of c-kit gene that might be involved in neoplastic growth or oncogenesis of some cell types, including mast cells.
19
Barnett, Christine M., and Michael C. Heinrich. "Management of Tyrosine Kinase Inhibitor–Resistant Gastrointestinal Stromal Tumors." American Society of Clinical Oncology Educational Book, no. 32 (June 2012): 663–68. http://dx.doi.org/10.14694/edbook_am.2012.32.66.
Повний текст джерелаАнотація:
Overview: The treatment of gastrointestinal stromal tumors (GISTs) has been a model for targeted cancer therapy. The discovery of driver somatic mutations in the KIT and PDGFRA receptor tyrosine kinases led to a shift of therapy from conventional cytotoxic chemotherapy to inhibitors of these receptors. Targeted molecular therapy of GIST has markedly increased the overall survival of patients with advanced disease. However, the ability of kinase therapy to control metastatic disease is ultimately limited by the ability of these agents to overcome intrinsic or acquired resistance mechanisms. Ongoing basic and clinical research is focusing on identifying new agents to inhibit KIT/PDGFRA kinase activity and/or other novel molecular targets in GIST.
20
Chan, Perry M., Subburaj Ilangumaran, Jose La Rose, Avijit Chakrabartty, and Robert Rottapel. "Autoinhibition of the Kit Receptor Tyrosine Kinase by the Cytosolic Juxtamembrane Region." Molecular and Cellular Biology 23, no. 9 (May 1, 2003): 3067–78. http://dx.doi.org/10.1128/mcb.23.9.3067-3078.2003.
Повний текст джерелаАнотація:
ABSTRACT Genetic studies have implicated the cytosolic juxtamembrane region of the Kit receptor tyrosine kinase as an autoinhibitory regulatory domain. Mutations in the juxtamembrane domain are associated with cancers, such as gastrointestinal stromal tumors and mastocytosis, and result in constitutive activation of Kit. Here we elucidate the biochemical mechanism of this regulation. A synthetic peptide encompassing the juxtamembrane region demonstrates cooperative thermal denaturation, suggesting that it folds as an autonomous domain. The juxtamembrane peptide directly interacted with the N-terminal ATP-binding lobe of the kinase domain. A mutation in the juxtamembrane region corresponding to an oncogenic form of Kit or a tyrosine-phosphorylated form of the juxtamembrane peptide disrupted the stability of this domain and its interaction with the N-terminal kinase lobe. Kinetic analysis of the Kit kinase harboring oncogenic mutations in the juxtamembrane region displayed faster activation times than the wild-type kinase. Addition of exogenous wild-type juxtamembrane peptide to active forms of Kit inhibited its kinase activity in trans, whereas the mutant peptide and a phosphorylated form of the wild-type peptide were less effective inhibitors. Lastly, expression of the Kit juxtamembrane peptide in cells which harbor an oncogenic form of Kit inhibited cell growth in a Kit-specific manner. Together, these results show the Kit kinase is autoinhibited through an intramolecular interaction with the juxtamembrane domain, and tyrosine phosphorylation and oncogenic mutations relieved the regulatory function of the juxtamembrane domain.
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Anzai, Naoyuki, Younghee Lee, Byung-S. Youn, Seiji Fukuda, Young-June Kim, Charlie Mantel, Makoto Akashi, and Hal E. Broxmeyer. "c-kit associated with the transmembrane 4 superfamily proteins constitutes a functionally distinct subunit in human hematopoietic progenitors." Blood 99, no. 12 (June 15, 2002): 4413–21. http://dx.doi.org/10.1182/blood.v99.12.4413.
Повний текст джерелаАнотація:
The transmembrane 4 superfamily (TM4SF) has come into prominence for its association with a wide range of cell surface molecules, especially integrins. We report that TM4SF molecules CD9, CD63, and CD81 are physically associated with c-kit receptor tyrosine kinase in the human factor–dependent myeloid cell line, MO7e. We characterized this complex using coimmunoprecipitation and colocalization methods. The c-kit coimmunoprecipitated with anti-TM4SF antibodies showed several distinct phenotypes compared to the total c-kit immunoprecipitated with anti–c-kit antibody. These included: (1) higher basal level of tyrosine phosphorylation without elevated kinase activity in the absence of Steel factor (SLF), (2) deficient enhancement of tyrosine phosphorylation and kinase activity in response to SLF, (3) elevated binding rate of SLF shown in chemical cross-linking studies, and (4) little internalization and degradation after SLF treatment. Cocapping studies in living cells showed that c-kit colocalized with TM4SF molecules after SLF stimulation, suggesting confirmation of the biochemical data obtained by the coimmunoprecipitation studies. Colocalization of c-kit with CD81 by SLF was also observed in cord blood CD34+ cells, suggesting the existence of functional units of c-kit in TM4SF complexes in primary hematopoietic cells. This suggests that some TM4SF members may negatively modulate function of c-kit receptor tyrosine kinase and thus regulate receptor sensitivity to SLF in hematopoietic progenitors.
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Tang, B., H. Mano, T. Yi, and J. N. Ihle. "Tec kinase associates with c-kit and is tyrosine phosphorylated and activated following stem cell factor binding." Molecular and Cellular Biology 14, no. 12 (December 1994): 8432–37. http://dx.doi.org/10.1128/mcb.14.12.8432-8437.1994.
Повний текст джерелаАнотація:
Stem cell factor (SCF) plays a crucial role in hematopoiesis through its interaction with the receptor tyrosine kinase c-kit. However, the signaling events that are activated by this interaction and involved in the control of growth or differentiation are not completely understood. We demonstrate here that Tec, a cytoplasmic, src-related kinase, physically associates with c-kit through a region that contains a proline-rich motif, amino terminal of the SH3 domain. Following SCF binding, Tec is tyrosine phosphorylated and its in vitro kinase activity is increased. Tyrosine phosphorylation of Tec is not detected in the response to other cytokines controlling hematopoiesis, including colony-stimulating factor-1 (CSF-1), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-3 (IL-3). Conversely, the cytoplasmic kinase JAK2 is activated by IL-3 but not by SCF stimulation. The activation of distinct cytoplasmic kinases may account for the synergy seen in the actions of SCF and IL-3 on hematopoietic stem cells.
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Tang, B., H. Mano, T. Yi, and J. N. Ihle. "Tec kinase associates with c-kit and is tyrosine phosphorylated and activated following stem cell factor binding." Molecular and Cellular Biology 14, no. 12 (December 1994): 8432–37. http://dx.doi.org/10.1128/mcb.14.12.8432.
Повний текст джерелаАнотація:
Stem cell factor (SCF) plays a crucial role in hematopoiesis through its interaction with the receptor tyrosine kinase c-kit. However, the signaling events that are activated by this interaction and involved in the control of growth or differentiation are not completely understood. We demonstrate here that Tec, a cytoplasmic, src-related kinase, physically associates with c-kit through a region that contains a proline-rich motif, amino terminal of the SH3 domain. Following SCF binding, Tec is tyrosine phosphorylated and its in vitro kinase activity is increased. Tyrosine phosphorylation of Tec is not detected in the response to other cytokines controlling hematopoiesis, including colony-stimulating factor-1 (CSF-1), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-3 (IL-3). Conversely, the cytoplasmic kinase JAK2 is activated by IL-3 but not by SCF stimulation. The activation of distinct cytoplasmic kinases may account for the synergy seen in the actions of SCF and IL-3 on hematopoietic stem cells.
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Galanis, A., and M. Levis. "Inhibition of c-Kit by tyrosine kinase inhibitors." Haematologica 100, no. 3 (November 25, 2014): e77-e79. http://dx.doi.org/10.3324/haematol.2014.117028.
Повний текст джерела
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Taniguchi, Yoshitaka, Roanna London, Karin Schinkmann, Shuxian Jiang, and Hava Avraham. "The Receptor Protein Tyrosine Phosphatase, PTP-RO, Is Upregulated During Megakaryocyte Differentiation and Is Associated With the c-Kit Receptor." Blood 94, no. 2 (July 15, 1999): 539–49. http://dx.doi.org/10.1182/blood.v94.2.539.
Повний текст джерелаАнотація:
Abstract We have recently isolated a cDNA encoding a novel human receptor-type tyrosine phosphatase, termed PTP-RO (for a protein tyrosine phosphatase receptor omicron), from 5-fluorouracil–treated murine bone marrow cells. PTP-RO is a human homologue of murine PTPλ and is related to the homotypically adhering κ and μ receptor-type tyrosine phosphatases. PTP-RO is expressed in human megakaryocytic cell lines, primary bone marrow megakaryocytes, and stem cells. PTP-RO mRNA and protein expression are upregulated upon phorbol 12-myristate 13-acetate (PMA) treatment of the megakaryocytic cell lines CMS, CMK, and Dami. To elucidate the function of PTP-RO in megakaryocytic cells and its potential involvement in the stem cell factor (SCF)/c-Kit receptor pathway, COS-7 and 293 cells were cotransfected with the cDNAs of both the c-Kit tyrosine kinase receptor and PTP-RO. PTP-RO was found to be associated with the c-Kit receptor in these transfected cells and the SCF/Kit ligand induced a rapid tyrosine phosphorylation of PTP-RO. Interestingly, these transfected cells demonstrated a decrease in their proliferative response to the SCF/Kit ligand. In addition, we assessed the association of PTP-RO with c-Kit in vivo. The results demonstrated that PTP-RO associates with c-Kit but not with the tyrosine kinase receptor FGF-R and that PTP-RO is tyrosine-phosphorylated after SCF stimulation of Mo7e and CMK cells. Antisense oligonucleotides directed against PTP-RO mRNA sequences significantly inhibited megakaryocyte progenitor proliferation. Therefore, these data show that the novel tyrosine kinase phosphatase PTP-RO is involved in megakaryocytopoiesis and that its function is mediated by the SCF/c-Kit pathway.
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Taniguchi, Yoshitaka, Roanna London, Karin Schinkmann, Shuxian Jiang, and Hava Avraham. "The Receptor Protein Tyrosine Phosphatase, PTP-RO, Is Upregulated During Megakaryocyte Differentiation and Is Associated With the c-Kit Receptor." Blood 94, no. 2 (July 15, 1999): 539–49. http://dx.doi.org/10.1182/blood.v94.2.539.414k40_539_549.
Повний текст джерелаАнотація:
We have recently isolated a cDNA encoding a novel human receptor-type tyrosine phosphatase, termed PTP-RO (for a protein tyrosine phosphatase receptor omicron), from 5-fluorouracil–treated murine bone marrow cells. PTP-RO is a human homologue of murine PTPλ and is related to the homotypically adhering κ and μ receptor-type tyrosine phosphatases. PTP-RO is expressed in human megakaryocytic cell lines, primary bone marrow megakaryocytes, and stem cells. PTP-RO mRNA and protein expression are upregulated upon phorbol 12-myristate 13-acetate (PMA) treatment of the megakaryocytic cell lines CMS, CMK, and Dami. To elucidate the function of PTP-RO in megakaryocytic cells and its potential involvement in the stem cell factor (SCF)/c-Kit receptor pathway, COS-7 and 293 cells were cotransfected with the cDNAs of both the c-Kit tyrosine kinase receptor and PTP-RO. PTP-RO was found to be associated with the c-Kit receptor in these transfected cells and the SCF/Kit ligand induced a rapid tyrosine phosphorylation of PTP-RO. Interestingly, these transfected cells demonstrated a decrease in their proliferative response to the SCF/Kit ligand. In addition, we assessed the association of PTP-RO with c-Kit in vivo. The results demonstrated that PTP-RO associates with c-Kit but not with the tyrosine kinase receptor FGF-R and that PTP-RO is tyrosine-phosphorylated after SCF stimulation of Mo7e and CMK cells. Antisense oligonucleotides directed against PTP-RO mRNA sequences significantly inhibited megakaryocyte progenitor proliferation. Therefore, these data show that the novel tyrosine kinase phosphatase PTP-RO is involved in megakaryocytopoiesis and that its function is mediated by the SCF/c-Kit pathway.
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Shi, Xiarong, Leiliane P. Sousa, Elizabeth M. Mandel-Bausch, Francisco Tome, Andrey V. Reshetnyak, Yaron Hadari, Joseph Schlessinger, and Irit Lax. "Distinct cellular properties of oncogenic KIT receptor tyrosine kinase mutants enable alternative courses of cancer cell inhibition." Proceedings of the National Academy of Sciences 113, no. 33 (August 1, 2016): E4784—E4793. http://dx.doi.org/10.1073/pnas.1610179113.
Повний текст джерелаАнотація:
Large genomic sequencing analysis as part of precision medicine efforts revealed numerous activating mutations in receptor tyrosine kinases, including KIT. Unfortunately, a single approach is not effective for inhibiting cancer cells or treating cancers driven by all known oncogenic KIT mutants. Here, we show that each of the six major KIT oncogenic mutants exhibits different enzymatic, cellular, and dynamic properties and responds distinctly to different KIT inhibitors. One class of KIT mutants responded well to anti-KIT antibody treatment alone or in combination with a low dose of tyrosine kinase inhibitors (TKIs). A second class of KIT mutants, including a mutant resistant to imatinib treatment, responded well to a combination of TKI with anti-KIT antibodies or to anti-KIT toxin conjugates, respectively. We conclude that the preferred choice of precision medicine treatments for cancers driven by activated KIT and other RTKs may rely on clear understanding of the dynamic properties of oncogenic mutants.
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Dastych, Jaroslaw, Dennis Taub, Mary C. Hardison, and Dean D. Metcalfe. "Tyrosine kinase-deficient Wvc-kit induces mast cell adhesion and chemotaxis." American Journal of Physiology-Cell Physiology 275, no. 5 (November 1, 1998): C1291—C1299. http://dx.doi.org/10.1152/ajpcell.1998.275.5.c1291.
Повний текст джерелаАнотація:
W/Wvmice are deficient in tissue mast cells, and mast cells cultured from these mice do not proliferate in response to the c-kit ligand, stem cell factor (SCF). In this paper, we report that mouse bone marrow cultured mast cells derived from W/Wvmice do adhere to fibronectin in the presence of SCF and exhibit chemotaxis to SCF, and we explore this model for the understanding of c-kit-mediated signaling pathways. Both in vitro and in vivo (in intact cells) phosphorylation experiments demonstrated a low residual level of W/Wvc-kit protein phosphorylation. SCF-induced responses in W/Wvmast cells were abolished by the tyrosine kinase inhibitor herbimycin A and by the phospatidylinositol 3-kinase (PI 3-kinase) inhibitor wortmannin but were not affected by protein kinase C inhibitors. These observations are consistent with the conclusions that Wvc-kit initiates a signaling process that is PI 3-kinase dependent and that mutated Wvc-kit retains the ability to initiate mast cell adhesion and migration.
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Heinrich, Michael C., Charles D. Blanke, Brian J. Druker, and Christopher L. Corless. "Inhibition of KIT Tyrosine Kinase Activity: A Novel Molecular Approach to the Treatment of KIT-Positive Malignancies." Journal of Clinical Oncology 20, no. 6 (March 15, 2002): 1692–703. http://dx.doi.org/10.1200/jco.2002.20.6.1692.
Повний текст джерелаАнотація:
PURPOSE: Activation of the KIT tyrosine kinase by somatic mutation has been documented in a number of human malignancies, including gastrointestinal stromal tumor (GIST), seminoma, acute myelogenous leukemia (AML), and mastocytosis. In addition, paracrine or autocrine activation of this kinase has been postulated in numerous other malignancies, including small-cell lung cancer and ovarian cancer. In this review, we discuss the rationale for and development of KIT tyrosine kinase inhibitors for the treatment of human malignancies. MATERIALS AND METHODS: Studies were identified through a MEDLINE search, review of bibliographies of relevant articles, and review of abstracts from national meetings. RESULTS: Four tyrosine kinase inhibitors that have activity against KIT are currently being used in clinical trials, and one, STI571, has recently been approved by the United States Food and Drug Administration for treating patients with chronic myelogenous leukemia. The role of KIT inhibitors in treating KIT-positive malignancies is reviewed. CONCLUSION: Targeted therapy to inhibit the kinase activity of KIT is a rational approach to the treatment of KIT-positive malignancies. Two key factors are the potency of a given inhibitor and the relative contribution of KIT activation to the growth of the tumor. Given our current understanding of KIT activity in human malignancy, the best candidate diseases for treatment with KIT inhibitors are GIST, mastocytosis, seminoma and possibly some cases of AML. Additionally, KIT inhibitors may play an adjunctive role in diseases such as small-cell lung cancer, in which KIT activation is secondary to ligand binding rather than an acquired mutation.
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Roberts, Riyaadh, and Dhirendra Govender. "Gene of the month: KIT." Journal of Clinical Pathology 68, no. 9 (July 1, 2015): 671–74. http://dx.doi.org/10.1136/jclinpath-2015-203207.
Повний текст джерелаАнотація:
Deranged pathway activation and KIT mutations occur in numerous solid and haematological malignancies, with gain-of-function mutations being the most common demonstrable abnormality. Through a complex series of interactions, activation of the KIT receptor tyrosine kinase leads to cell survival, evasion of apoptosis, angiogenesis, dysregulated cell cycle control and promotion of tumourigenesis. The KIT receptor tyrosine kinase is a well-studied therapeutic target in human malignancies. The KIT mutational status of a neoplasm plays an important role in predicting the response to targeted therapies. In this article we outline the structure, function and mutations of the KIT gene, its role in various neoplasms, therapeutic impacts and the role that these play in clinical patient outcome.
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Iqbal, Nida, and Naveed Iqbal. "Imatinib: A Breakthrough of Targeted Therapy in Cancer." Chemotherapy Research and Practice 2014 (May 19, 2014): 1–9. http://dx.doi.org/10.1155/2014/357027.
Повний текст джерелаАнотація:
Deregulated protein tyrosine kinase activity is central to the pathogenesis of human cancers. Targeted therapy in the form of selective tyrosine kinase inhibitors (TKIs) has transformed the approach to management of various cancers and represents a therapeutic breakthrough. Imatinib was one of the first cancer therapies to show the potential for such targeted action. Imatinib, an oral targeted therapy, inhibits tyrosine kinases specifically BCR-ABL, c-KIT, and PDGFRA. Apart from its remarkable success in CML and GIST, Imatinib benefits various other tumors caused by Imatinib-specific abnormalities of PDGFR and c-KIT. Imatinib has also been proven to be effective in steroid-refractory chronic graft-versus-host disease because of its anti-PDGFR action. This paper is a comprehensive review of the role of Imatinib in oncology.
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Miyazawa, K., DA Williams, A. Gotoh, J. Nishimaki, HE Broxmeyer, and K. Toyama. "Membrane-bound Steel factor induces more persistent tyrosine kinase activation and longer life span of c-kit gene-encoded protein than its soluble form." Blood 85, no. 3 (February 1, 1995): 641–49. http://dx.doi.org/10.1182/blood.v85.3.641.bloodjournal853641.
Повний текст джерелаАнотація:
Alternative splicing of exon 6 results in the production of two isoforms of Steel factor (SLF): the membrane-bound and soluble forms. To investigate differences in the kinetics of c-kit tyrosine kinase activated by these two isoforms, we used a stromal cell line (SI/SI4) established from SI/SI homozygous murine embryo fetal liver and its stable transfectants containing either hSCF248 cDNA (including exon 6; secreted form) or hSCF220 cDNA (lacking exon 6; membrane-bound form) as the source of each isoform. Interaction of factor dependent myeloid cell line MO7e with stromal cells producing either isoform resulted in activated c-kit tyrosine kinase and induction of the same series of tyrosine phosphorylated cellular proteins in MO7e cells. However, SI4- h220 (membrane-bound form) induced more persistent activation of c-kit kinase than SI4-h248 (soluble form) did. Flow cytometric analysis and pulse-chase studies using [35S]methionine showed that SI4-h248 induced rapid downmodulation of cell-surface c-kit expression and its protein degradation in MO7e cells, whereas SI4-h220 induced more prolonged life span of c-kit protein. Addition of soluble recombinant human SLF to SI4- h220 cultures enhanced reduction of cell-surface c-kit expression and its protein degradation. Because the kinetics of c-kit inactivation strikingly fits with the protein degradation rates of c-kit under the conditions described above, rapid proteolysis of c-kit protein induced by soluble SLF stimulation may function as a “turn-off switch” for activated c-kit kinase.
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Voisset, Edwige, Sophie Lopez, Patrice Dubreuil, and Paulo De Sepulveda. "The tyrosine kinase FES is an essential effector of KITD816V proliferation signal." Blood 110, no. 7 (October 1, 2007): 2593–99. http://dx.doi.org/10.1182/blood-2007-02-076471.
Повний текст джерелаАнотація:
KIT is a tyrosine kinase receptor that is aberrantly activated in several neoplasms. In human pathologies, the most frequent mutation of KIT occurs at codon 816. The resulting KIT mutant protein is activated in the absence of ligand and is resistant to the clinically available inhibitors of KIT. In this report, we provide evidence for an essential function of the cytoplasmic tyrosine kinase FES downstream of KITD816V. FES is phosphorylated on tyrosine residues in cells that carry KITD816V mutation, and this phosphorylation is KIT dependent. Reduction of FES expression using RNA interference results in decreased cell proliferation in human or murine cells harboring KITD816V or the homologous mouse mutation KITD814Y. The reduced cell growth can be rescued using another cytokine (granulocyte-macrophage colony-stimulating factor [GM-CSF]) and is not observed when the closely related fer gene is targeted. Finally, signaling downstream of KITD816V is altered in cells lacking FES expression. This study shows a major function of FES downstream of activated KIT receptor and thereby points to FES as a novel target in KIT-related pathologies.
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Samayawardhena, Lionel, and Andrew W. B. Craig. "Involvement of Fps/Fes and Fer Kinases in c-Kit Signalling in Mast Cells and Mast Cell Leukemias." Blood 106, no. 11 (November 16, 2005): 3887. http://dx.doi.org/10.1182/blood.v106.11.3887.3887.
Повний текст джерелаАнотація:
Abstract The c-Kit receptor protein-tyrosine kinase (PTK) is required for mast cell differentiation and function. Signalling by c-Kit normally depends on binding its ligand, Stem Cell Factor (SCF). However, several constitutively activating mutations in c-Kit have been described in myeloid leukemias (including mast cell leukemias (MCLs)) and in solid tumors. The objective of this study is to define the involvement of two non-receptor PTKs called Fps/Fes (hereafter referred to as Fps) and Fer in c-Kit signaling in mast cells and MCLs. Recent studies using transgenic mouse strains bearing kinase-inactivating or null mutations in Fer and Fps have revealed roles in hematopoiesis, and in limiting the innate immune response. Recently, we showed that Fer and Fps are activated downstream of the high affinity IgE receptor, FcεRI, in bone marrow-derived mast cells (BMMCs), and that Fer kinase is required for sustained p38 Mitogen-activated protein kinase (MAPK) activation and chemotaxis upon activation of either FcεRI or c-Kit. In this study, we focus on the roles of Fer and Fps in c-Kit signaling in BMMCs. SCF-induced c-Kit activation led to rapid association of both kinases with c-Kit, and increased tyrosine phosphorylation of Fer and Fps. Interestingly, kinase-dead Fps protein was also phosphorylated upon c-Kit activation, suggesting the involvement of an upstream kinase. Pretreatment of BMMCs with the Src family kinase inhibitor SU6656, caused reduced phosphorylation of Fer and Fps upon SCF treatment. This suggests an involvement of one or more Src family kinases (SFKs) in phosphorylating Fps and Fer upon c-Kit activation. We next examined the potential involvement of the Fyn SFK, since it is known to interact with a juxtamembrane site in activated c-Kit and has been linked to Fer activation in other cell types. SCF treatment of BMMCs from Fyn knock-out mice (fyn-null) revealed normal activation of c-Kit, Erk MAPK, but reduced phosphorylation of Fer kinase. Furthermore, we have observed reduced phosphorylation of Shp2 phosphatase, and the p38 and Jnk MAPKs in Fyn-null BMMCs compared to control. We are currently attempting to restore Fyn expression by retroviral transduction to attempt to rescue these signalling defects, and also evaluate potential requirements for Fyn in chemotaxis and cytokine production. Using MCL cell lines harbouring constitutively actived c-Kit (RBL-2H3 and HMC-1), we have observed that phosphorylation of Fer and Fps kinases are inhibited by treating cells with either a c-Kit inhibitor (SU11652) or SFK inhibitor (SU6656). In conclusion, Fer and Fps kinases participate in c-Kit signaling in normal and leukemic mast cells, and Src family kinases likely contribute to their activation. Using mast cells from Fer/Fps-deficient mice, we will identify their downstream targets and determine if they are required for leukemogenesis by an activated c-Kit transgene.
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Loriaux, Marc, Ross Levine, Jeffrey Tyner, Stephan Frohling, Claudia Scholl, Eric Stoffregen, Gerlinde Wernig, et al. "High-Throughput Sequence Analysis of the Tyrosine Kinome in Acute Myeloid Leukemia." Blood 110, no. 11 (November 16, 2007): 886. http://dx.doi.org/10.1182/blood.v110.11.886.886.
Повний текст джерелаАнотація:
Abstract Mutations that result in constitutive tyrosine kinase activation occur in a wide spectrum of human malignancies, including acute myeloid leukemia (AML). Although activating mutations in the tyrosine kinases FLT3 and c-KIT occur in a significant proportion of patients with AML, the genomic events responsible for oncogenic signaling in most patients with AML have not been identified. To determine whether other aberrantly activated tyrosine kinases contribute to the pathogenesis of AML, we employed high throughput (HT) DNA sequence analysis to screen the exons encoding domains implicated in kinase activation (activation loop), and autoinhibition (juxtamembrane domains) in 85 tyrosine kinase genes in 192 AML patients without FLT3 or c-KIT mutations. The screen identified 34 non-synonymous sequence variations in 25 different kinases that had not been reported in single-nucleotide polymorphism (SNP) databases. These included a novel activating allele in FLT3, and a previously described activating mutation in MET (METT1010I). The majority of the novel sequence variants were cloned into their respective tyrosine kinase cDNA, and stably expressed in the factor-dependent Ba/F3 hematopoietic cell line. Apart from one FLT3 allele, none of the other novel variants showed evidence of constitutive phosphorylation by immunoblot analysis, and none transformed Ba/F3 cell lines to factor independent growth. These findings indicate that the majority of these alleles are not potent activators of tyrosine kinase activity in this cellular context, and that a significant proportion of non-synonymous sequence variants identified in HT DNA sequencing screens may not have functional significance. Although several explanations are possible for this observation, these data are consistent with recent reports that a significant fraction of such sequence variants are “passenger” rather than “driver” alleles, in cancer, and underscore the importance of functional assessment of candidate disease alleles.
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LAM, Lily P. Y., Rowena Y. K. CHOW, and Stuart A. BERGER. "A transforming mutation enhances the activity of the c-Kit soluble tyrosine kinase domain." Biochemical Journal 338, no. 1 (February 8, 1999): 131–38. http://dx.doi.org/10.1042/bj3380131.
Повний текст джерелаАнотація:
An activating mutation (DY814) located in the catalytic domain of the c-Kit receptor has been found in mastocytomas from human, mouse and rat. We evaluated the enzymic properties of purified wild-type (WT) and DY814 tyrosine kinase domains expressed in Pichia pastoris. A linker encoding the Flag epitope was fused to c-Kit cDNA species, enabling affinity purification of the proteins with anti-Flag antibodies. Yeast lysates expressing DY814 contained multiple tyrosine-phosphorylated proteins, whereas WT lysates had no detectable tyrosine phosphorylation. Purification of the WT and mutant kinases in the presence of vanadate demonstrated that both enzymes undergo autophosphorylation. Kinetic analyses of WT and DY814 kinases indicated that at 20 nM enzyme concentration the mutation increases the specific activity 10-fold and decreases the apparent Km for ATP 9-fold. WT activity displayed a hyperbolic dependence on enzyme concentration, consistent with a requirement for dimerization or aggregation for activity. This activity was also enhanced by anti-Flag antibodies. In contrast, the dependence of DY814 activity on enzyme concentration was primarily linear and only marginally enhanced by anti-Flag antibodies. Gel-filtration analysis showed that the WT kinase migrated as a monomer, whereas the DY814 mutant migrated as a dimer. These results indicate that this point mutation promotes dimerization of the c-Kit kinase, potentially contributing to its transforming potential in mast cells.
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Zeng, Shan, Zhiheng Xu, Stan Lipkowitz, and Jack B. Longley. "Regulation of stem cell factor receptor signaling by Cbl family proteins (Cbl-b/c-Cbl)." Blood 105, no. 1 (January 1, 2005): 226–32. http://dx.doi.org/10.1182/blood-2004-05-1768.
Повний текст джерелаАнотація:
Abstract Activation of the KIT receptor tyrosine kinase contributes to the pathogenesis of several human diseases, but the mechanisms regulating KIT signaling have not been fully characterized. Here, we show that stem cell factor (SCF), the ligand for KIT, induces the interaction between KIT and Cbl proteins and their mutual degradation. Upon SCF stimulation, KIT binds to and induces the phosphorylation of Cbl proteins, which in turn act as E3 ligases, mediating the ubiquitination and degradation of KIT and themselves. Tyrosine kinase binding and RING finger domains of Cbl are essential for Cbl-mediated ubiquitination and degradation of KIT. We propose a negative feedback loop controlling the SCF-KIT signaling pathway, in which SCF activates KIT. The activated KIT in turn induces phosphorylation and activation of Cbl proteins. The Cbl proteins then bind and direct the degradation of activated KIT, leading to down-regulation of KIT signaling. (Blood. 2005;105:226-232)
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Reboll, Marc R., Stefanie Klede, Manuel H. Taft, Chen-Leng Cai, Loren J. Field, Kory J. Lavine, Andrew L. Koenig, et al. "Meteorin-like promotes heart repair through endothelial KIT receptor tyrosine kinase." Science 376, no. 6599 (June 17, 2022): 1343–47. http://dx.doi.org/10.1126/science.abn3027.
Повний текст джерелаАнотація:
Effective tissue repair after myocardial infarction entails a vigorous angiogenic response, guided by incompletely defined immune cell–endothelial cell interactions. We identify the monocyte- and macrophage-derived cytokine METRNL (meteorin-like) as a driver of postinfarction angiogenesis and high-affinity ligand for the stem cell factor receptor KIT (KIT receptor tyrosine kinase). METRNL mediated angiogenic effects in cultured human endothelial cells through KIT-dependent signaling pathways. In a mouse model of myocardial infarction, METRNL promoted infarct repair by selectively expanding the KIT-expressing endothelial cell population in the infarct border zone. Metrnl -deficient mice failed to mount this KIT-dependent angiogenic response and developed severe postinfarction heart failure. Our data establish METRNL as a KIT receptor ligand in the context of ischemic tissue repair.
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Hirata, T., E. Morii, M. Morimoto, T. Kasugai, T. Tsujimura, S. Hirota, Y. Kanakura, S. Nomura, and Y. Kitamura. "Stem cell factor induces outgrowth of c-kit-positive neurites and supports the survival of c-kit-positive neurons in dorsal root ganglia of mouse embryos." Development 119, no. 1 (September 1, 1993): 49–56. http://dx.doi.org/10.1242/dev.119.1.49.
Повний текст джерелаАнотація:
The c-kit receptor tyrosine kinase is highly expressed by about 10% of the neurons in the dorsal root ganglia (DRGs) of mouse embryos. We investigated the in vitro effect of stem cell factor (SCF), the ligand for c-kit receptor, on DRGs. Recombinant murine SCF (rmSCF) induced the outgrowth of c-kit-positive neurites from DRGs of normal (+/+) embryos. The effect of SCF was dose dependent and completely abolished by anti-c-kit ACK2 monoclonal antibody (mAb). Some neurites whose outgrowth was induced by nerve growth factor (NGF) were c-kit-positive, but anti-NGF mAb did not inhibit the rmSCF-induced neurite outgrowth. rmSCF did not induce neurite outgrowth from DRGs of W/W embryos that did not express c-kit receptors on the cell surface and of W42/W42 mutant embryos that expressed c-kit receptors without tyrosine kinase activity. rmSCF also had a trophic effect on c-kit-positive neurons in the culture of dissociated DRG cells. Most c-kit-positive neurons appeared to respond to NGF as well, and the SCF-responsive subpopulation represented about 10% of NGF-responsive neurons. rmSCF did not support the survival of DRG neurons from embryos of W/W and W42/W42 genotypes. These results suggest that the stimulus through the c-kit receptor tyrosine kinase has an important role in development of the peripheral nervous system.
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Fawzy, Ahmed, Samira Mahmoud Abd Allah, Mostafa Mohammed Salem, and Lobna Omar Al Farouk. "Immunohistochemical and Histopathological Study of Anaplastic Lymphoma Kinase and Tyrosine-kinase Receptor Expression in Bronchogenic Carcinoma." Open Access Macedonian Journal of Medical Sciences 9, A (February 18, 2021): 106–13. http://dx.doi.org/10.3889/oamjms.2021.5671.
Повний текст джерелаАнотація:
BACKGROUND: Adenocarcinoma of the lung is the most common tumor type of primary lung cancer and is characterized by heterogeneity on the molecular, clinical, and pathological levels. The presence of an anaplastic lymphoma kinase (ALK) fusion oncogene defines a molecular subset of non-small cell lung cancer with distinct clinical and pathologic features. Furthermore, the tyrosine-kinase receptor (C-kit) is considered to be expressed in various solid tumors, including carcinomas of the lung.
AIM: This study aims to correlate immunohistochemical (IHC) expression of ALK and C-kit with pathological features of lung carcinoma and to correlate IHC expression of ALK with IHC expression of C-kit in lung carcinoma.
MATERIALS AND METHODS: The material of this study consists of paraffin blocks of 60 cases of patients with bronchogenic carcinoma, IHC staining with ALK and C-kit then analysis of immunoreactivity scoring was done.
RESULTS: As regards ALK expression, 3 (5%) cases showed positive expression of ALK and 57 (95%) cases showed negative expression of ALK with no statistically significant correlation between the ALK expression and the histopathological type. While C-kit expression, 4 (6.7%) cases showed positive expression and 56 (93.3%) cases showed negative expression of C-kit with statistically significant correlation between the C-kit expression and the histopathological type.
CONCLUSION: There is an association between expression of c-kit and tumor histological type in lung carcinoma. Expression was notably significant among adenocarcinomas and small cell carcinomas.
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Funasaka, Y., T. Boulton, M. Cobb, Y. Yarden, B. Fan, S. D. Lyman, D. E. Williams, D. M. Anderson, R. Zakut, and Y. Mishima. "c-Kit-kinase induces a cascade of protein tyrosine phosphorylation in normal human melanocytes in response to mast cell growth factor and stimulates mitogen-activated protein kinase but is down-regulated in melanomas." Molecular Biology of the Cell 3, no. 2 (February 1992): 197–209. http://dx.doi.org/10.1091/mbc.3.2.197.
Повний текст джерелаАнотація:
The proto-oncogene c-Kit, a transmembrane receptor tyrosine kinase, is an important regulator of cell growth whose constitutively active oncogenic counterpart, v-kit, induces sarcomas in cats. Mutations in murine c-kit that reduce the receptor tyrosine kinase activity cause deficiencies in the migration and proliferation of melanoblasts, hematopoietic stem cells, and primordial germ cells. We therefore investigated whether c-Kit regulates normal human melanocyte proliferation and plays a role in melanomas. We show that normal human melanocytes respond to mast cell growth factor (MGF), the Kit-ligand that stimulates phosphorylation of tyrosyl residues in c-Kit and induces sequential phosphorylation of tyrosyl residues in several other proteins. One of the phosphorylated intermediates in the signal transduction pathway was identified as an early response kinase (mitogen-activated protein [MAP] kinase). Dephosphorylation of a prominent 180-kDa protein suggests that MGF also activates a phosphotyrosine phosphatase. In contrast, MGF did not induce proliferation, the cascade of protein phosphorylations, or MAP kinase activation in the majority of cells cultured from primary nodular and metastatic melanomas that grow independently of exogenous factors. In the five out of eight human melanoma lines expressing c-kit mRNAs, c-Kit was not constitutively activated. Therefore, although c-Kit-kinase is a potent growth regulator of normal human melanocytes, its activity is not positively associated with malignant transformation.
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Klug, Lillian Rose, Jeffrey Tyner, and Michael C. Heinrich. "LMTK3 as a novel regulator of oncogenic KIT in KIT-mutant cancers." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 11044. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.11044.
Повний текст джерелаАнотація:
11044 Background: Multiple cancers, such as gastrointestinal stromal tumors (GIST) and melanoma, have been shown to be caused by somatic activating mutations in the receptor tyrosine kinase KIT. The major cause of death in patients with advanced KIT -mutant cancers is due to the development of KIT tyrosine kinase inhibitor-resistant (TKI-resistant) metastatic disease. Drug resistance arises almost exclusively from secondary mutations within KIT, highlighting the importance of KIT in the proliferation and survival of these tumors. Methods: We performed a human kinase siRNA screen in multiple KIT -mutant cancer cell lines using viability as a read out. We defined candidate targets as those whose knockdown decreased viability in all cell lines. Validation and mechanistic studies were done using a library of KIT-mutant GIST and melanoma cells. Results: We identified lemur tyrosine kinase 3 (LMTK3) as candidate target in three KIT -mutant cell lines. LMTK3 silencing reduced the viability of all KIT -mutant GIST and melanoma cells tested to date, including cell lines with KIT TKI-resistance mutations. Importantly, LMTK3 silencing decreased the viability of KIT -mutant cells specifically, but not that of KIT-independent GIST and melanoma cells. Further, we found that decreased cell viability was due to induction of apoptosis, as assessed by measuring caspase 3 and 7 activity within 96 hours of LMTK3 silencing. LMTK3 knockdown also reduced tumor growth in vivo in a GIST xenograft model. Because these cells depend so heavily on KIT and the loss of KIT signaling results in cell death, we hypothesized that LMTK3 silencing may affect this pathway. Indeed, LMTK3 silencing decreased levels of autophosphorylated KIT. We also observed a significant decrease in total KIT protein expression. This phenotype and corresponding viability was rescued with exogenous expression of full length LMTK3. Conclusions: LMTK3 is an important regulator of oncogenic KIT expression and activity in KIT-mutant GIST and melanoma and represents a novel, tractable target.
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Tyner, Jeffrey W., Denise K. Walters, Stephanie G. Willis, Mary Luttropp, Jason Oost, Marc Loriaux, Heidi Erickson, et al. "RNAi screening of the tyrosine kinome identifies therapeutic targets in acute myeloid leukemia." Blood 111, no. 4 (February 15, 2008): 2238–45. http://dx.doi.org/10.1182/blood-2007-06-097253.
Повний текст джерелаАнотація:
Despite vast improvements in our understanding of cancer genetics, a large percentage of cancer cases present without knowledge of the causative genetic events. Tyrosine kinases are frequently implicated in the pathogenesis of numerous types of cancer, but identification and validation of tyrosine kinase targets in cancer can be a time-consuming process. We report the establishment of an efficient, functional screening assay using RNAi technology to directly assess and compare the effect of individually targeting each member of the tyrosine kinase family. We demonstrate that siRNA screening can identify tyrosine kinase targets containing activating mutations in Janus kinase (JAK) 3 (A572V) in CMK cells and c-KIT (V560G) in HMC1.1 cells. In addition, this assay identifies targets that do not contain mutations, such as JAK1 and the focal adhesion kinases (FAK), that are crucial to the survival of the cancer cells. This technique, with additional development, might eventually offer the potential to match specific therapies with individual patients based on a functional assay.
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Dhillon, Sohita. "Ripretinib: First Approval." Drugs 80, no. 11 (June 23, 2020): 1133–38. http://dx.doi.org/10.1007/s40265-020-01348-2.
Повний текст джерелаАнотація:
AbstractRipretinib (QINLOCK™) is a novel type II tyrosine switch control inhibitor being developed by Deciphera Pharmaceuticals for the treatment of KIT proto-oncogene receptor tyrosine kinase (KIT)-driven and/or platelet derived growth factor receptor A (PDGFRA)-driven cancers, including gastrointestinal stromal tumour (GIST). Ripretinib inhibits KIT and PDGFRA kinase, including wild-type, primary and secondary mutations, as well as other kinases, such as PDGFRB, TIE2, VEGFR2 and BRAF. In May 2020, oral ripretinib received its first approval in the USA for the treatment of adult patients with advanced GIST who have received prior treatment with ≥ 3 kinase inhibitors, including imatinib. The US FDA, Health Canada and the Australian Therapeutic Goods Administration collaborated on the review of the ripretinib new drug application in this indication as part of Project Orbis; regulatory review in Australia and Canada is ongoing. Clinical development for GIST, solid tumours and systemic mastocytosis is underway in several countries worldwide. This article summarizes the milestones in the development of ripretinib leading to this first approval for the treatment of advanced GIST.
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Growney, Joseph D., Jennifer J. Clark, Jennifer Adelsperger, Richard Stone, Doriano Fabbro, James D. Griffin, and D. Gary Gilliland. "Activation mutations of human c-KIT resistant to imatinib mesylate are sensitive to the tyrosine kinase inhibitor PKC412." Blood 106, no. 2 (July 15, 2005): 721–24. http://dx.doi.org/10.1182/blood-2004-12-4617.
Повний текст джерелаАнотація:
Abstract Constitutively activated forms of the transmembrane receptor tyrosine kinase c-KIT have been associated with systemic mast cell disease, acute myeloid leukemia, and gastrointestinal stromal tumors. Reports of the resistance of the kinase domain mutation D816V to the adenosine triphosphate (ATP)-competitive kinase inhibitor imatinib mesylate prompted us to characterize 14 c-KIT mutations reported in association with human hematologic malignancies for transforming activity in the murine hematopoietic cell line Ba/F3 and for sensitivity to the tyrosine kinase inhibitor PKC412. Ten of 14 c-KIT mutations conferred interleukin 3 (IL-3)-independent growth. c-KIT D816Y and D816V transformed cells were sensitive to PKC412 despite resistance to imatinib mesylate. In these cells, PKC412, but not imatinib mesylate, inhibited autophosphorylation of c-KIT and activation of downstream effectors signal transducer and transcriptional activator 5 (Stat5) and Stat3. Variable sensitivities to PKC412 or imatinib mesylate were observed among other mutants. These findings suggest that PKC412 may be a useful therapeutic agent for c-KIT-positive malignancies harboring the imatinib mesylate-resistant D816V or D816Y activation mutations. (Blood. 2005;106:721-724)
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Taylor, Marcia L., Jaroslaw Dastych, Devinder Sehgal, Magnus Sundstrom, Gunnar Nilsson, Cem Akin, Rose G. Mage, and Dean D. Metcalfe. "The Kit-activating mutation D816V enhances stem cell factor–dependent chemotaxis." Blood 98, no. 4 (August 15, 2001): 1195–99. http://dx.doi.org/10.1182/blood.v98.4.1195.
Повний текст джерелаАнотація:
The D816V mutation of c-kit has been detected in patients with mastocytosis. This mutation leads to constitutive tyrosine kinase activation of Kit. Because stem cell factor (SCF), the ligand for Kit (CD117+), is a chemoattractant for CD117+ cells and one feature of mastocytosis is an abnormal collection of mast cells in tissues derived from CD34+CD117+ mast cell precursors, the hypothesis was considered that the D816V mutation would enhance chemotaxis of these precursor cells. Constructs encoding wild-type Kit or Kit bearing the D816V mutation were transfected into Jurkat cells, labeled with Calcein-am, and migration to SCF assessed in the presence or absence of tyrosine kinase inhibitors. Chemotaxis to SCF was enhanced in D816V transfectants compared to wild-type Kit transfectants (P < .002). Migration of both transfectants was inhibited by tyrosine kinase inhibitors, although D816V transfectants were more sensitive. Chemotaxis was next performed on CD34+CD117+ circulating mast cell precursors obtained from patients with mastocytosis. Analysis of prechemotaxis and migrated cells showed that whereas less than 10% in the prechemotaxis sample had the D816V mutation, 40% to 80% of migrated cells had this mutation. These results demonstrate that the D816V Kit mutation enhances chemotaxis of CD117+ cells, offering one explanation for increased mast cells observed in tissues of patients with mastocytosis.
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McGlade, C. J., C. Ellis, M. Reedijk, D. Anderson, G. Mbamalu, A. D. Reith, G. Panayotou, P. End, A. Bernstein, and A. Kazlauskas. "SH2 domains of the p85 alpha subunit of phosphatidylinositol 3-kinase regulate binding to growth factor receptors." Molecular and Cellular Biology 12, no. 3 (March 1992): 991–97. http://dx.doi.org/10.1128/mcb.12.3.991-997.1992.
Повний текст джерелаАнотація:
The binding of cytoplasmic signaling proteins such as phospholipase C-gamma 1 and Ras GTPase-activating protein to autophosphorylated growth factor receptors is directed by their noncatalytic Src homology region 2 (SH2) domains. The p85 alpha regulatory subunit of phosphatidylinositol (PI) 3-kinase, which associates with several receptor protein-tyrosine kinases, also contains two SH2 domains. Both p85 alpha SH2 domains, when expressed individually as fusion proteins in bacteria, bound stably to the activated beta receptor for platelet-derived growth factor (PDGF). Complex formation required PDGF stimulation and was dependent on receptor tyrosine kinase activity. The bacterial p85 alpha SH2 domains recognized activated beta PDGF receptor which had been immobilized on a filter, indicating that SH2 domains contact autophosphorylated receptors directly. Several receptor tyrosine kinases within the PDGF receptor subfamily, including the colony-stimulating factor 1 receptor and the Steel factor receptor (Kit), also associate with PI 3-kinase in vivo. Bacterially expressed SH2 domains derived from the p85 alpha subunit of PI 3-kinase bound in vitro to the activated colony-stimulating factor 1 receptor and to Kit. We infer that the SH2 domains of p85 alpha bind to high-affinity sites on these receptors, whose creation is dependent on receptor autophosphorylation. The SH2 domains of p85 are therefore primarily responsible for the binding of PI 3-kinase to activated growth factor receptors.
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McGlade, C. J., C. Ellis, M. Reedijk, D. Anderson, G. Mbamalu, A. D. Reith, G. Panayotou, P. End, A. Bernstein, and A. Kazlauskas. "SH2 domains of the p85 alpha subunit of phosphatidylinositol 3-kinase regulate binding to growth factor receptors." Molecular and Cellular Biology 12, no. 3 (March 1992): 991–97. http://dx.doi.org/10.1128/mcb.12.3.991.
Повний текст джерелаАнотація:
The binding of cytoplasmic signaling proteins such as phospholipase C-gamma 1 and Ras GTPase-activating protein to autophosphorylated growth factor receptors is directed by their noncatalytic Src homology region 2 (SH2) domains. The p85 alpha regulatory subunit of phosphatidylinositol (PI) 3-kinase, which associates with several receptor protein-tyrosine kinases, also contains two SH2 domains. Both p85 alpha SH2 domains, when expressed individually as fusion proteins in bacteria, bound stably to the activated beta receptor for platelet-derived growth factor (PDGF). Complex formation required PDGF stimulation and was dependent on receptor tyrosine kinase activity. The bacterial p85 alpha SH2 domains recognized activated beta PDGF receptor which had been immobilized on a filter, indicating that SH2 domains contact autophosphorylated receptors directly. Several receptor tyrosine kinases within the PDGF receptor subfamily, including the colony-stimulating factor 1 receptor and the Steel factor receptor (Kit), also associate with PI 3-kinase in vivo. Bacterially expressed SH2 domains derived from the p85 alpha subunit of PI 3-kinase bound in vitro to the activated colony-stimulating factor 1 receptor and to Kit. We infer that the SH2 domains of p85 alpha bind to high-affinity sites on these receptors, whose creation is dependent on receptor autophosphorylation. The SH2 domains of p85 are therefore primarily responsible for the binding of PI 3-kinase to activated growth factor receptors.
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Edling, Charlotte E., and Bengt Hallberg. "c-Kit—A hematopoietic cell essential receptor tyrosine kinase." International Journal of Biochemistry & Cell Biology 39, no. 11 (January 2007): 1995–98. http://dx.doi.org/10.1016/j.biocel.2006.12.005.
Повний текст джерела
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Verstovsek, Srdan, Cem Akin, Giles J. Francis, Manshouri Taghi, Ly Huynh, Paul W. Manley, Leila Alland, Margaret Dugan, Jorge E. Cortes, and Kantarjian M. Hagop. "Effects of AMN107, a Novel Aminopyrimidine Tyrosine Kinase Inhibitor, on Human Mast Cells Bearing Wild-Type or Mutated Codon 816 c-kit." Blood 106, no. 11 (November 16, 2005): 3528. http://dx.doi.org/10.1182/blood.v106.11.3528.3528.
Повний текст джерелаАнотація:
Abstract Background. Majority of adult patients with systemic mastocytosis (SM) have activating mutation in codon 816 of c-kit (CD117), a receptor on the surface of mast cells. This abnormality is responsible for the pathogenesis of the disease. Methods. We investigated the effects of a newly designed tyrosine kinase inhibitor, AMN107, by comparing its in vitro inhibitory potency on c-kit mutated mast cell lines and patient samples with that of imatinib mesylate, another tyrosine kinase inhibitor, effective in some patients with SM. Two cell lines, subclones of HMC-1 cells, were used: HMC-1560 carrying juxtamembrane domain mutation in codon 560 of c-kit, and HMC-1560, 816 carrying both codon 560 mutation and tyrosine kinase domain mutation in codon 816 of c-kit. Results. In HMC-1560 mast cell line carrying wild-type codon 816, AMN107 was as potent as imatinib in inhibiting cellular proliferation, with IC50 values of 108 and 74 nM respectively, while in HMC-1560, 816 cell line carrying 816 mutation, neither medication had an effect. AMN107 was also as effective as imatinib in inhibiting phosphorylation of c-kit tyrosine kinase in HMC-1560 cells. The inhibition of cellular proliferation was associated with induction of apoptosis in HMC-1560 cells. AMN107 in concentrations up to 1 uM had no effect on bone marrow mast cells carrying D816V c-kit mutation obtained from patients with mastocytosis. Conclusions. Our results suggest similar potency of AMN107 and imatinib in mast cells that carry wild-type codon 816, but no activity against codon 816 mutation carrying cells.