Journal articles: 'Arg tyrosine kinase'

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Tanis, Keith Q., Darren Veach, Henry S. Duewel, William G. Bornmann, and Anthony J. Koleske. "Two Distinct Phosphorylation Pathways Have Additive Effects on Abl Family Kinase Activation." Molecular and Cellular Biology 23, no. 11 (June 1, 2003): 3884–96. http://dx.doi.org/10.1128/mcb.23.11.3884-3896.2003.

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ABSTRACT The activities of the related Abl and Arg nonreceptor tyrosine kinases are kept under tight control in cells, but exposure to several different stimuli results in a two- to fivefold stimulation of kinase activity. Following the breakdown of inhibitory intramolecular interactions, Abl activation requires phosphorylation on several tyrosine residues, including a tyrosine in its activation loop. These activating phosphorylations have been proposed to occur either through autophosphorylation by Abl in trans or through phosphorylation of Abl by the Src nonreceptor tyrosine kinase. We show here that these two pathways mediate phosphorylation at distinct sites in Abl and Arg and have additive effects on Abl and Arg kinase activation. Abl and Arg autophosphorylate at several sites outside the activation loop, leading to 5.2- and 6.2-fold increases in kinase activity, respectively. We also find that the Src family kinase Hck phosphorylates the Abl and Arg activation loops, leading to an additional twofold stimulation of kinase activity. The autoactivation pathway may allow Abl family kinases to integrate or amplify cues relayed by Src family kinases from cell surface receptors.

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Okuda, Keiko, Ellen Weisberg, D. Gary Gilliland, and James D. Griffin. "ARG tyrosine kinase activity is inhibited by STI571." Blood 97, no. 8 (April 15, 2001): 2440–48. http://dx.doi.org/10.1182/blood.v97.8.2440.

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Abstract The tyrosine kinase inhibitor STI571 inhibits BCR/ABL and induces hematologic remission in most patients with chronic myeloid leukemia. In addition to BCR/ABL, STI571 also inhibits v-Abl, TEL/ABL, the native platelet-derived growth factor (PDGF)β receptor, and c-KIT, but it does not inhibit SRC family kinases, c-FMS, FLT3, the epidermal growth factor receptor, or multiple other tyrosine kinases. ARG is a widely expressed tyrosine kinase that shares substantial sequence identity with c-ABL in the kinase domain and cooperates with ABL to regulate neurulation in the developing mouse embryo. As described here, ARG has recently been implicated in the pathogenesis of leukemia as a fusion partner of TEL. A TEL/ARG fusion was constructed to determine whether ARG can be inhibited by STI571. When expressed in the factor-dependent murine hematopoietic cell line Ba/F3, the TEL/ARG protein was heavily phosphorylated on tyrosine, increased tyrosine phosphorylation of multiple cellular proteins, and induced factor-independent proliferation. The effects of STI571 on Ba/F3 cells transformed with BCR/ABL, TEL/ABL, TEL/PDGFβR, or TEL/ARG were then compared. STI571 inhibited tyrosine phosphorylation and cell growth of Ba/F3 cells expressing BCR/ABL, TEL/ABL, TEL/PDGFβR, and TEL/ARG with an IC50 of approximately 0.5 μM in each case, but it had no effect on untransformed Ba/F3 cells growing in IL-3 or on Ba/F3 cells transformed by TEL/JAK2. Culture of TEL/ARG-transfected Ba/F3 cells with IL-3 completely prevented STI571-induced apoptosis in these cells, similar to what has been observed with BCR/ABL- or TEL/ABL-transformed cells. These results indicate that ARG is a target of the small molecule, tyrosine kinase inhibitor STI571.

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Ha, Byung Hak, Mark Adam Simpson, Anthony J. Koleske, and Titus J. Boggon. "Structure of the ABL2/ARG kinase in complex with dasatinib." Acta Crystallographica Section F Structural Biology Communications 71, no. 4 (March 20, 2015): 443–48. http://dx.doi.org/10.1107/s2053230x15004793.

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ABL2/ARG (ABL-related gene) belongs to the ABL (Abelson tyrosine-protein kinase) family of tyrosine kinases. ARG plays important roles in cell morphogenesis, motility, growth and survival, and many of these biological roles overlap with the cellular functions of the ABL kinase. Chronic myeloid leukemia (CML) is associated with constitutive ABL kinase activation resulting from fusion between parts of the breakpoint cluster region (BCR) andABL1genes. Similarly, fusion of theETV6(Tel) andARGgenes drives some forms of T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). Dasatinib is a tyrosine kinase inhibitor used for the treatment of CML by inhibiting ABL, and while it also inhibits ARG, there is currently no structure of ARG in complex with dasatinib. Here, the co-crystal structure of the mouse ARG catalytic domain with dasatinib at 2.5 Å resolution is reported. Dasatinib-bound ARG is found in the DFG-in conformation although it is nonphosphorylated on the activation-loop tyrosine. In this structure the glycine-rich P-loop is found in a relatively open conformation compared with other known ABL family–inhibitor complex structures.

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Plattner, Rina, Anthony J. Koleske, Andrius Kazlauskas, and Ann Marie Pendergast. "Bidirectional Signaling Links the Abelson Kinases to the Platelet-Derived Growth Factor Receptor." Molecular and Cellular Biology 24, no. 6 (March 15, 2004): 2573–83. http://dx.doi.org/10.1128/mcb.24.6.2573-2583.2004.

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ABSTRACT The c-Abl nonreceptor tyrosine kinase is activated by growth factor signals such as the platelet-derived growth factor (PDGF) and functions downstream of the PDGF-β receptor (PDGFR) to mediate biological processes such as membrane ruffling, mitogenesis, and chemotaxis. Here, we show that the related kinase Arg is activated downstream of PDGFRs in a manner dependent on Src family kinases and phospholipase C γ1 (PLC-γ1)-mediated phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis, as we showed previously for c-Abl. PIP2, a highly abundant phosphoinositide known to regulate cytoskeletal and membrane proteins, inhibits the tyrosine kinase activities of both Arg and c-Abl in vitro and in cells. We now demonstrate that c-Abl and Arg form inducible complexes with and are phosphorylated by the PDGFR tyrosine kinase in vitro and in vivo. Moreover, c-Abl and Arg, in turn, phosphorylate the PDGFR. We show that c-Abl and Arg exhibit nonredundant functions downstream of the activated PDGFR. Reintroduction of c-Abl into Arg-Abl double-null fibroblasts rescues the ability of PLC-γ1 to increase PDGF-mediated chemotaxis, while reexpression of Arg fails to rescue the chemotaxis defect. These data show that, although both kinases are activated and form complexes with proteins in the PDGFR signaling pathway, only c-Abl functions downstream of PLC-γ1 to mediate chemotaxis.

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Moresco, Eva Marie Yang, Alfred J. Scheetz, William G. Bornmann, Anthony J. Koleske, and Reiko Maki Fitzsimonds. "Abl Family Nonreceptor Tyrosine Kinases Modulate Short-Term Synaptic Plasticity." Journal of Neurophysiology 89, no. 3 (March 1, 2003): 1678–87. http://dx.doi.org/10.1152/jn.00892.2002.

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Abl family nonreceptor tyrosine kinases regulate cell morphogenesis through functional interactions with the actin cytoskeleton. The vertebrate Abl family kinases, Abl and Arg, are expressed in the adult mouse brain, where they may regulate actin cytoskeletal dynamics in mature neurons. Using immunoelectron microscopy, we have localized Abl and Arg to the pre- and postsynaptic compartments of synapses in the mouse hippocampal area CA1. Paired-pulse facilitation (PPF) was significantly reduced at the Schaffer collateral-CA1 (SC-CA1) excitatory synapses in hippocampal slices from abl−/− and arg−/− mice as compared with wild-type mice. Furthermore, treatment of wild-type slices with the specific Abl family kinase inhibitor STI571 also reduced PPF. Basal synaptic transmission, posttetanic potentiation (PTP), long-term potentiation (LTP), and long-term depression (LTD) were similar to wild-type controls in abl−/− and arg−/− slices and in STI571-treated wild-type slices. These results indicate that an important function of Abl and Arg is to modulate synaptic efficacy via a presynaptic mechanism during repetitive activation.

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Peacock, Justin G., Ann L. Miller, William D. Bradley, Olga C. Rodriguez, Donna J. Webb, and Anthony J. Koleske. "The Abl-related Gene Tyrosine Kinase Acts through p190RhoGAP to Inhibit Actomyosin Contractility and Regulate Focal Adhesion Dynamics upon Adhesion to Fibronectin." Molecular Biology of the Cell 18, no. 10 (October 2007): 3860–72. http://dx.doi.org/10.1091/mbc.e07-01-0075.

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In migrating cells, actin polymerization promotes protrusion of the leading edge, whereas actomyosin contractility powers net cell body translocation. Although they promote F-actin–dependent protrusions of the cell periphery upon adhesion to fibronectin (FN), Abl family kinases inhibit cell migration on FN. We provide evidence here that the Abl-related gene (Arg/Abl2) kinase inhibits fibroblast migration by attenuating actomyosin contractility and regulating focal adhesion dynamics. arg−/− fibroblasts migrate at faster average speeds than wild-type (wt) cells, whereas Arg re-expression in these cells slows migration. Surprisingly, the faster migrating arg−/− fibroblasts have more prominent F-actin stress fibers and focal adhesions and exhibit increased actomyosin contractility relative to wt cells. Interestingly, Arg requires distinct functional domains to inhibit focal adhesions and actomyosin contractility. The kinase domain–containing Arg N-terminal half can act through the RhoA inhibitor p190RhoGAP to attenuate stress fiber formation and cell contractility. However, Arg requires both its kinase activity and its cytoskeleton-binding C-terminal half to fully inhibit focal adhesions. Although focal adhesions do not turn over efficiently in the trailing edge of arg−/− cells, the increased contractility of arg−/− cells tears the adhesions from the substrate, allowing for the faster migration observed in these cells. Together, our data strongly suggest that Arg inhibits cell migration by restricting actomyosin contractility and regulating its coupling to the substrate through focal adhesions.

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Yokota, Asumi, Hideyo Hirai, Tsukimi Shoji, Taira Maekawa, and Keiko Okuda. "C-Terminal Domain of ABL Family Kinases, ABL and ARG, Defines Their Distinct Leukemogenic Activities in Vivo." Blood 124, no. 21 (December 6, 2014): 2368. http://dx.doi.org/10.1182/blood.v124.21.2368.2368.

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Abstract ARG (ABL2) is a member of ABL family kinases and highly homologous to ABL (ABL1) except the C-terminal domain adjacent to the kinase domain. TEL/ARG that consists of ARG fused to TEL (ETV6) has been found in AML M3, M4 or T-ALL patients, with additional chromosomal abnormalities of t(15;17)(q12;q21), inv(16)(p13;q12) or t(1;10;12)(q25;q23;p13) translocation, respectively. The structure of TEL/ARG is similar to that of TEL/ABL, which has been found in patients with T-ALL, B-ALL, AML and CML. TEL mediates homo-oligomerization of these fusion proteins, TEL/ABL and TEL/ARG, resulting in constitutive activation of the tyrosine kinases. Although ABL fusion proteins such as BCR/ABL and TEL/ABL have been intensively investigated, the involvement of TEL/ARG in leukemogenesis is not fully elucidated yet. We have recently reported that in vitro transforming activity of TEL/ARG was significantly lower than that of TEL/ABL although their kinase activities were almost identical. Interestingly, the in vitro transforming activities of C-terminus-swapped mutants, TEL/ABL with C-terminal domain of ARG [TEL-ABL (ARG-C)] or TEL/ARG with C-terminal domain of ABL [TEL/ARG (ABL-C)], were comparable to those of TEL/ARG or TEL/ABL, respectively, while kinase activities in the swapped mutants were not altered. These results suggest that C-termini of ABL family kinases contain some functional domain that defines their distinct transforming activities. The purpose of this study is to compare the in vivo leukemogenic activities of TEL/ABL and TEL/ARG, and evaluate the impact of the C-terminal domains. First, we investigated whether TEL/ABL or TEL/ARG caused leukemia in mice. Each fusion gene together with GFP gene was retrovirally transduced into the bone marrow cells harvested from C57BL/6 mice treated with 5-fluorouracil, and the transduced cells were transplanted into lethally irradiated mice. Similar to BCR/ABL, transplantation of TEL/ABL-transduced cells induced rapid myeloproliferative status accompanied by hepatomegaly and/or splenomegaly, and all the recipient mice died within 33 days after transplantation, indicating the development of myeloid leukemia. In contrast, the recipient mice transplanted with TEL/ARG-transduced cells did not develop myeloid leukemia but infiltrative mastocytosis, and died around 200 days after transplantation (Figure 1). Hemophagocytic mast cells accumulating in the bone marrow, and mast cells circulating in the peripheral blood were also observed in these mice. Next we investigated the roles of C-terminal domains of ABL and ARG in their in vivo leukemogenic activities. C-terminus-swapped mutants, TEL/ABL (ARG-C) and TEL/ARG (ABL-C) were retrovirally transduced into bone marrow cells and the transduced cells were transplanted as described above. Intriguingly, TEL/ABL (ARG-C) mutant failed to cause myeloproliferative status or leukemia at day 153 (Figure 2A). On the other hand, TEL/ARG (ABL-C) induced lethal myeloid leukemia in 4 out of 13 mice (30.8%) within 111 days after transplantation (Figure 2B). Collectively, the in vivo phenotypes induced by TEL/ABL (ARG-C) or TEL/ARG (ABL-C) resembled those induced by TEL/ARG or TEL/ABL, respectively. Mastocytosis, a characteristic of TEL-ARG-induced phenotype, has not been observed so far in any of the recipients of TEL/ABL (ARG-C) or TEL/ARG (ABL-C). In conclusion, these results indicate that C-terminal domain of ABL family kinases defines their distinct leukemogenic activities in vivo through modulating both proliferation and differentiation. Notably, C-terminus of ARG strongly suppressed the in vivo leukemogenic activity of TEL/ABL without impairing the tyrosine kinase activity. Further clarification of the molecular mechanisms underlying the suppressive activity of C-terminus of ARG will lead to development of a novel therapeutic strategy, especially for patients with CML harboring mutations, which are resistant to tyrosine kinase inhibitors. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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Okuda, Keiko, Nari Harakawa, Richard A. VanEtten, Nihal Patel, Naochika Domae, Yuko Sato, and Hideyo Hirai. "Distinct Transforming and Leukemogenic Activities of Tel-Arg and Tel-Abl Oncogenes in Mice: Possible Negative Role for the Transforming Activity in C-Terminus of Arg." Blood 112, no. 11 (November 16, 2008): 2845. http://dx.doi.org/10.1182/blood.v112.11.2845.2845.

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Abstract ARG (ABL2) is a member of ABL tyrosine kinase gene family that is highly homologous to c-ABL (ABL1) in overall domain structure (SH3-SH2-SH1) and amino acid sequence. ARG has recently been implicated in the pathogenesis of human acute leukemia though t(1;12) translocations that fuse a transcription factor gene, ETV6/TEL, to ARG (Iijima et al., Blood2000;95:2126). The resulting TEL-ARG fusion tyrosine kinase is similar in structure to the TEL-ABL fusion found in some acute leukemia and atypical CML patients, and, like TEL-ABL, can transform Ba/F3 cells and fibroblasts in vitro and activate a similar set of intracellular signaling pathways (Iijima et al., Oncogene2002;21:4374). To assess the leukemogenic activity of TEL-ARG, we co-expressed TEL-ARG with GFP in mouse bone marrow using a retroviral bone marrow transduction/transplantation strategy. Whereas TEL-ABL induces rapidly fatal myelolproliferative disease (MPD) in recipient mice (Million et al., Blood2000;96:664), recipients of TEL-ARG-transduced BM did not develop overt MPD, but succumbed instead to long-latency (30–45 weeks) T-cell acute lymphoblastic leukemia/lymphoma characterized by modest leukocytosis and a malignant pleural effusion composed of Thy-1+B220- tumor cells. To study the molecular basis of the marked difference in the leukemogenic activity of TEL-ARG and TEL-ABL, we produced TEL-ARG mutants that swapped the kinase domain or C-terminus of ARG with the corresponding domain in ABL. The mutants were introduced into Ba/F3 cells by retroviral transduction and transduced cells selected for equal expression of the fusion protein by flow sorting for populations with equivalent intensity of GFP fluorescence. All chimeric proteins were expressed and showed equivalent levels of auto-phosphorylation by western blot analysis of the sorted cells. However, the quantitative transforming activity of TEL-ARG in Ba/F3 cells, measured by the number of days required to achieve measurable cell growth following IL-3 deprivation, was significantly lower than for TEL-ABL (25 ± 4.3 days for TEL-ARG vs. 1 to 2 days for TEL-ABL). A TEL-ARG mutant containing the ABL kinase domain was similar to TEL-ARG in this assay, but replacing the ARG C-terminal domain with that of ABL increased Ba/F3 transformation to levels equivalent to TEL-ABL. To further dissect the functional domains that are responsible for this effect, a new series of mutants containing internal deletions in ARG C-terminus of TEL-ARG [aa.826–976 (Delta Box1), aa.977–1213 (Delta Box2), aa 1214–1316 (Delta Box3), aa.1317–1465 (Delta Box4)] were generated. Regarding to their function, only Box2 and Box4 were reported as F- or F,G- actin binding domain. From a preliminary study using the cell lines which express each of the mutants, Delta Box 1 clones obtained an accelerated proliferation which compared with that of Tel-Abl, suggesting that there is a disadvantage for cell proliferation by ARG c-terminus. These results indicate that distinct bio-phenotype associated with Abl family tyrosine kinase is the most likely regulated by their c-terminus and the c-terminus of Arg contains functional subdomain that impairs growth signal induced by Abl family tyrosine kinase.

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Cao, Cheng, Xinping Ren, Surender Kharbanda, Anthony Koleske, K. V. S. Prasad, and Donald Kufe. "The ARG Tyrosine Kinase Interacts with Siva-1 in the Apoptotic Response to Oxidative Stress." Journal of Biological Chemistry 276, no. 15 (February 23, 2001): 11465–68. http://dx.doi.org/10.1074/jbc.c100050200.

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The Abl family of mammalian nonreceptor tyrosine kinases consists of c-Abl and ARG (Abl-related gene). Certain insights are available regarding the involvement c-Abl in the response of cells to stress. ARG, however, has no known function in cell signaling. The present studies demonstrate that ARG associates with the proapoptotic Siva-1 protein. The functional significance of the ARG-Siva-1 interaction is supported by the finding that ARG is activated by oxidative stress and that this response involves ARG-mediated phosphorylation of Siva-1 on Tyr48. The proapoptotic effects of Siva-1 are accentuated in cells stably expressing ARG and are inhibited in ARG-deficient cells. Moreover, the proapoptotic effects of Siva-1 are abrogated by mutation of the Tyr48site. We also show that the apoptotic response to oxidative stress is attenuated in ARG-deficient cells and that this defect is corrected by reconstituting ARG expression. These findings support a model in which the activation of ARG by oxidative stress induces apoptosis by a Siva-1-dependent mechanism.

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Swimm, Alyson, Bettina Bommarius, Yue Li, David Cheng, Patrick Reeves, Melanie Sherman, Darren Veach, William Bornmann, and Daniel Kalman. "EnteropathogenicEscherichia coliUse Redundant Tyrosine Kinases to Form Actin Pedestals." Molecular Biology of the Cell 15, no. 8 (August 2004): 3520–29. http://dx.doi.org/10.1091/mbc.e04-02-0093.

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Enteropathogenic Escherichia coli (EPEC) are deadly contaminants in water and food and induce protrusion of actin-rich membrane pedestals beneath themselves upon attachment to intestinal epithelia. EPEC then causes intestinal inflammation, diarrhea, and, among children, death. Here, we show that EPEC uses multiple tyrosine kinases for formation of pedestals, each of which is sufficient but not necessary. In particular, we show that Abl and Arg, members of the Abl family of tyrosine kinases, localize and are activated in pedestals. We also show that pyrido[2,3-d]pyrimidine (PD) compounds, which inhibit Abl, Arg, and related kinases, block pedestal formation. Finally, we show that Abl and Arg are sufficient for pedestal formation in the absence of other tyrosine kinase activity, but they are not necessary. Our results suggest that additional kinases that are sensitive to inhibition by PD also can suffice. Together, these results suggest that EPEC has evolved a mechanism to use any of several functionally redundant tyrosine kinases during pathogenesis, perhaps facilitating its capacity to infect different cell types. Moreover, PD compounds are being developed to treat cancers caused by dysregulated Abl. Our results raise the possibility that PD may be useful in treating EPEC infections, and because PD affects host and not bacterium, selecting resistant strains may be far less likely than with conventional antibiotics.

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Li, Yingzhu, Hiroko Shimizu, Shuang-Lin Xiang, Yoshiro Maru, Noriaki Takao, and Ken-ichi Yamamoto. "Arg tyrosine kinase is involved in homologous recombinational DNA repair." Biochemical and Biophysical Research Communications 299, no. 5 (December 2002): 697–702. http://dx.doi.org/10.1016/s0006-291x(02)02692-x.

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Galkin, Vitold E., Albina Orlova, Anthony J. Koleske, and Edward H. Egelman. "The Arg Non-receptor Tyrosine Kinase Modifies F-actin Structure." Journal of Molecular Biology 346, no. 2 (February 2005): 565–75. http://dx.doi.org/10.1016/j.jmb.2004.11.078.

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Mulyati, Budi, Sri Sutjiningtyas, and Herlina. "STUDY IN SILICO OF THIOUREA-DERIVED COMPOUNDS AS TYROSINE KINASE RECEPTOR INHIBITORS." Jurnal Kimia Riset 7, no. 2 (December 9, 2022): 182–93. http://dx.doi.org/10.20473/jkr.v7i2.40036.

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Cancer is a disease caused by protein mutations, which cause cells to proliferate uncontrollably. Inhibiting the action of protein kinases is one method of preventing the signal that initiates the process of uncontrolled cell proliferation. This research aimed to determine the affinity of thiourea-derived compound ligands with the protein tyrosine kinase enzyme (PDB ID: 5LMA). The binding energy between each ligand and the tyrosine kinase receptor ranged from -87,62 to -95,26 kcal/mol. The percentage of ligand interactions varies above 80%. On the active site of the amino acid residues Leu 456, Leu 495, Ala 496, Ala 497, Arg 498, and Val 500, the tyrosine kinase enzyme binds to the ligands of thiourea-derived compounds via hydrogen, pi alkyl, and alkyl bonds. Pharmacokinetic, toxicity, and Lipinski regulation of thiourea-derived compounds yielded significant results as anticancer drug candidates.

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Ly, Kim Thien, and James E. Casanova. "Abelson Tyrosine Kinase Facilitates Salmonella enterica Serovar Typhimurium Entry into Epithelial Cells." Infection and Immunity 77, no. 1 (October 20, 2008): 60–69. http://dx.doi.org/10.1128/iai.00639-08.

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ABSTRACT The intracellular gram-negative bacterial pathogen Salmonella enterica serovar Typhimurium gains entry into nonphagocytic cells by manipulating the assembly of the host actin cytoskeleton. S. enterica serovar Typhimurium entry requires a functional type III secretion system, a conduit through which bacterial effector proteins are directly translocated into the host cytosol. We and others have previously reported the enhancement of tyrosine kinase activities during Salmonella serovar Typhimurium infection; however, neither specific kinases nor their targets have been well characterized. In this study, we investigated the roles of the cellular Abelson tyrosine kinase (c-Abl) and the related protein Arg in the context of serovar Typhimurium infection. We found that bacterial internalization was inhibited by more than 70% in cells lacking both c-Abl and Arg and that treatment of wild-type cells with a pharmaceutical inhibitor of the c-Abl kinase, STI571 (imatinib), reduced serovar Typhimurium invasion efficiency to a similar extent. Bacterial infection led to enhanced phosphorylation of two previously identified c-Abl substrates, the adaptor protein CT10 regulator of kinase (CrkII) and the Abelson-interacting protein Abi1, a component of the WAVE2 complex. Furthermore, overexpression of the nonphosphorylatable form of CrkII resulted in decreased invasion. Taken together, these findings indicate that c-Abl is activated during S. enterica serovar Typhimurium infection and that its phosphorylation of multiple downstream targets is functionally important in bacterial internalization.

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Cazzaniga, Giovanni, Sabrina Tosi, Alessandra Aloisi, Giovanni Giudici, Maria Daniotti, Pietro Pioltelli, Lyndal Kearney, and Andrea Biondi. "The Tyrosine Kinase Abl-Related Gene ARG Is Fused toETV6 in an AML-M4Eo Patient With a t(1;12)(q25;p13): Molecular Cloning of Both Reciprocal Transcripts." Blood 94, no. 12 (December 15, 1999): 4370–73. http://dx.doi.org/10.1182/blood.v94.12.4370.

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Abstract The Ets variant gene 6 (ETV6/TEL) gene is rearranged in the majority of patients with 12p13 translocations fused to a number of different partners. We present here a case of acute myeloid leukemia M4 with eosinophilia (AML-M4Eo) positive for the CBFb/MYH11 rearrangement and carrying a t(1;12)(q25;p13) that involves the ETV6 gene at 12p13. By 3′rapid amplification of cDNA ends-polymerase chain reaction (3′RACE-PCR), a novel fusion transcript was identified between the ETV6 and the Abelson-related gene (ARG) at 1q25, resulting in a chimeric protein consisting of the HLH oligomerization domain of ETV6 and the SH2, SH3, and protein tyrosine kinase (PTK) domains of ARG. The reciprocal transcript ARG-ETV6 was also detected in the patient RNA by reverse transcriptase-polymerase chain reaction (RT-PCR), although at a lower expression level. The ARG gene encodes for a nonreceptor tyrosine kinase characterized by high homology with c-Abl in the TK, SH2, and SH3 domains. This is the first report on ARGinvolvement in a human malignancy.

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Cazzaniga, Giovanni, Sabrina Tosi, Alessandra Aloisi, Giovanni Giudici, Maria Daniotti, Pietro Pioltelli, Lyndal Kearney, and Andrea Biondi. "The Tyrosine Kinase Abl-Related Gene ARG Is Fused toETV6 in an AML-M4Eo Patient With a t(1;12)(q25;p13): Molecular Cloning of Both Reciprocal Transcripts." Blood 94, no. 12 (December 15, 1999): 4370–73. http://dx.doi.org/10.1182/blood.v94.12.4370.424k34_4370_4373.

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The Ets variant gene 6 (ETV6/TEL) gene is rearranged in the majority of patients with 12p13 translocations fused to a number of different partners. We present here a case of acute myeloid leukemia M4 with eosinophilia (AML-M4Eo) positive for the CBFb/MYH11 rearrangement and carrying a t(1;12)(q25;p13) that involves the ETV6 gene at 12p13. By 3′rapid amplification of cDNA ends-polymerase chain reaction (3′RACE-PCR), a novel fusion transcript was identified between the ETV6 and the Abelson-related gene (ARG) at 1q25, resulting in a chimeric protein consisting of the HLH oligomerization domain of ETV6 and the SH2, SH3, and protein tyrosine kinase (PTK) domains of ARG. The reciprocal transcript ARG-ETV6 was also detected in the patient RNA by reverse transcriptase-polymerase chain reaction (RT-PCR), although at a lower expression level. The ARG gene encodes for a nonreceptor tyrosine kinase characterized by high homology with c-Abl in the TK, SH2, and SH3 domains. This is the first report on ARGinvolvement in a human malignancy.

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Miura, O., Y. Miura, N. Nakamura, FW Quelle, BA Witthuhn, JN Ihle, and N. Aoki. "Induction of tyrosine phosphorylation of Vav and expression of Pim-1 correlates with Jak2-mediated growth signaling from the erythropoietin receptor." Blood 84, no. 12 (December 15, 1994): 4135–41. http://dx.doi.org/10.1182/blood.v84.12.4135.bloodjournal84124135.

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The receptor for erythropoietin (Epo) belongs to the cytokine receptor family and lacks a tyrosine kinase domain. However, it has been hypothesized that a tyrosine kinase, Jak2, associates with the membrane proximal cytoplasmic region of Epo receptor (EpoR) and mediates the growth signaling from the receptor through tyrosine phosphorylation of cellular substrates. To explore the growth signaling pathways from the EpoR, we analyzed substrates of tyrosine phosphorylation induced by Epo stimulation in cells expressing various mutant EpoRs. The vav proto- oncogene product was found to be tyrosine phosphorylated after Epo stimulation in cells expressing the wild-type EpoR or a truncated receptor, H mutant, that retains the growth signaling function. In these cells, Epo also induced the expression of a serine/threonine kinase, Pim-1. However, Epo stimulation did not have any effect on Vav or Pim-1 in cells expressing a mutant EpoR, PM4 mutant, inactivated by a point mutation, Trp282 to Arg, in the membrane proximal region, which abrogates the interaction with Jak2. On the other hand, both tyrosine phosphorylation of Vav and expression of Pim-1 were observed constitutively in cells expressing a mutant EpoR that is constitutively activated by a point mutation, Arg 129 to Cys, in the extracellular domain. Jak2 was also constitutively tyrosine phosphorylated and activated in cells expressing this mutant, which confirms the crucial role of Jak2 in growth signaling from the EpoR. Taken together, these observations suggest that the tyrosine phosphorylation of Vav and the expression of Pim-1 may play important roles in growth signaling from the EpoR.

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Borowski, Peter, Kerstin Resch, Herbert Schmitz, and Max Heiland. "A Synthetic Peptide Derived from the Non-Structural Protein 3 of Hepatitis C Virus Serves as a Specific Substrate for PKC." Biological Chemistry 381, no. 1 (January 28, 2000): 19–27. http://dx.doi.org/10.1515/bc.2000.003.

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AbstractA synthetic peptide corresponding to the amino acid sequence Arg1487-Arg-Gly-Arg-Thr-Gly-Arg-Gly-Arg-Arg-Gly-Ile-Tyr-Arg1500of the hepatitis C virus (HCV) polyprotein was found to be a selective substrate for protein kinase C (PKC). In the presence of Ca2+, TPA and phospholipid, PKC phosphorylates the peptide [termed HCV(1487–1500)] with aKmof 11μM andVmaxof 24 μmol × min−1× mg−1. HCV(1487–1500) acts as a competitive inhibitor of PKC towards other peptide or protein substrates and inhibits the kinase activity with an IC50corresponding to theKmvalues measured for the substrates. N- or C-terminally deleted analogs of HCV(1487–1500) did not show inhibitory effects and were only marginally or not phosphorylatable.We designed an additional peptide in which the tyrosine residue was replaced by phenylalanine ([Phe1499]HCV(1487–1500)). This peptide was neither phosphorylated by other serine/threonine kinases tested nor by whole cell extracts prepared from PKC-depleted cells. [Phe1499]HCV(1487–1500) was used to monitor the TPA-induced translocation of PKC activity to the particulate fraction in JB6 cells. The use of SDS/PAGE to separate the peptide from ATP and Piallowed to monitor simultaneously PKC autophosphorylation and phosphorylation of the peptide. The data presented here show that [Phe1499]HCV(1487–1500) can serve as a convenient tool for investigations of PKC activity also in the presence of other kinases in tissues or in crude cell extracts.

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Bonacci, Gustavo, Jason Fletcher, Madhav Devani, Harsh Dwivedi, Ray Keller, and Chenbei Chang. "The cytoplasmic tyrosine kinase Arg regulates gastrulation via control of actin organization." Developmental Biology 364, no. 1 (April 2012): 42–55. http://dx.doi.org/10.1016/j.ydbio.2012.01.008.

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20

Mondino, A., S. Giordano, and P. M. Comoglio. "Defective posttranslational processing activates the tyrosine kinase encoded by the MET proto-oncogene (hepatocyte growth factor receptor)." Molecular and Cellular Biology 11, no. 12 (December 1991): 6084–92. http://dx.doi.org/10.1128/mcb.11.12.6084-6092.1991.

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The MET proto-oncogene encodes a 190-kDa disulfide-linked heterodimeric receptor (p190 alpha beta) whose tyrosine kinase activity is triggered by the hepatocyte growth factor. The mature receptor is made of two subunits: an alpha chain of 50 kDa and a beta chain of 145 kDa, arising from proteolytic cleavage of a single-chain precursor of 170 kDa (pr170). In a colon carcinoma cell line (LoVo), the precursor is not cleaved and the Met protein is exposed at the cell surface as a single-chain polypeptide of 190 kDa (p190NC). The expression of the uncleaved Met protein is due to defective posttranslational processing, since in this cell line (i) the proteolytic cleavage site Lys-303-Arg-Lys-Lys-Arg-Ser-308 is present in the precursor, (ii) p190NC is sensitive to mild trypsin digestion of the cell surface, generating alpha and beta chains of the correct size, and (iii) the 205-kDa insulin receptor precursor is not cleaved as well. p190NC is a functional tyrosine kinase in vitro and is activated in vivo, as shown by constitutive autophosphorylation on tyrosine. The MET gene is neither amplified nor rearranged in LoVo cells. Overlapping cDNA clones selected from a library derived from LoVo mRNA were sequenced. No mutations were present in the MET-coding region. These data indicate that the tyrosine kinase encoded by the MET proto-oncogene can be activated as a consequence of a posttranslational defect.

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Mondino, A., S. Giordano, and P. M. Comoglio. "Defective posttranslational processing activates the tyrosine kinase encoded by the MET proto-oncogene (hepatocyte growth factor receptor)." Molecular and Cellular Biology 11, no. 12 (December 1991): 6084–92. http://dx.doi.org/10.1128/mcb.11.12.6084.

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The MET proto-oncogene encodes a 190-kDa disulfide-linked heterodimeric receptor (p190 alpha beta) whose tyrosine kinase activity is triggered by the hepatocyte growth factor. The mature receptor is made of two subunits: an alpha chain of 50 kDa and a beta chain of 145 kDa, arising from proteolytic cleavage of a single-chain precursor of 170 kDa (pr170). In a colon carcinoma cell line (LoVo), the precursor is not cleaved and the Met protein is exposed at the cell surface as a single-chain polypeptide of 190 kDa (p190NC). The expression of the uncleaved Met protein is due to defective posttranslational processing, since in this cell line (i) the proteolytic cleavage site Lys-303-Arg-Lys-Lys-Arg-Ser-308 is present in the precursor, (ii) p190NC is sensitive to mild trypsin digestion of the cell surface, generating alpha and beta chains of the correct size, and (iii) the 205-kDa insulin receptor precursor is not cleaved as well. p190NC is a functional tyrosine kinase in vitro and is activated in vivo, as shown by constitutive autophosphorylation on tyrosine. The MET gene is neither amplified nor rearranged in LoVo cells. Overlapping cDNA clones selected from a library derived from LoVo mRNA were sequenced. No mutations were present in the MET-coding region. These data indicate that the tyrosine kinase encoded by the MET proto-oncogene can be activated as a consequence of a posttranslational defect.

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22

Perego, R., D. Ron, and G. Kruh. "Arg, A 145 Kd protein with tyrosine kinase activity belongs to the Abelson sub-family of non receptor tyrosine kinases." European Journal of Cancer and Clinical Oncology 27 (January 1991): S68. http://dx.doi.org/10.1016/0277-5379(91)91462-r.

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Miller, Ann L., Yinxiang Wang, Mark S. Mooseker, and Anthony J. Koleske. "The Abl-related gene (Arg) requires its F-actin–microtubule cross-linking activity to regulate lamellipodial dynamics during fibroblast adhesion." Journal of Cell Biology 165, no. 3 (May 10, 2004): 407–20. http://dx.doi.org/10.1083/jcb.200308055.

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Microtubules (MTs) help establish and maintain cell polarity by promoting actin-dependent membrane protrusion at the leading edge of the cell, but the molecular mechanisms that mediate cross-talk between actin and MTs during this process are unclear. We demonstrate that the Abl-related gene (Arg) nonreceptor tyrosine kinase is required for dynamic lamellipodial protrusions after adhesion to fibronectin. arg−/− fibroblasts exhibit reduced lamellipodial dynamics as compared with wild-type fibroblasts, and this defect can be rescued by reexpression of an Arg-yellow fluorescent protein fusion. We show that Arg can bind MTs with high affinity and cross-link filamentous actin (F-actin) bundles and MTs in vitro. MTs concentrate and insert into Arg-induced F-actin–rich cell protrusions. Arg requires both its F-actin–binding domains and its MT-binding domain to rescue the defects in lamellipodial dynamics of arg−/− fibroblasts. These findings demonstrate that Arg can mediate physical contact between F-actin and MTs at the cell periphery and that this cross-linking activity is required for Arg to regulate lamellipodial dynamics in fibroblasts.

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Chang, Chenbei, Jason Fletcher, Harshit Dwivedi, Madhav Devani, and Gustavo Bonacci. "The cytoplasmic tyrosine kinase Arg regulates Xenopus gastrulation via the adaptor protein CrkII." Developmental Biology 344, no. 1 (August 2010): 450. http://dx.doi.org/10.1016/j.ydbio.2010.05.153.

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25

Jacobsen, Freja Aksel, Alexander N. Scherer, Jeppe Mouritsen, Hera Bragadóttir, B. Thomas Bäckström, Samra Sardar, Dan Holmberg, Anthony J. Koleske, and Åsa Andersson. "A Role for the Non-Receptor Tyrosine Kinase Abl2/Arg in Experimental Neuroinflammation." Journal of Neuroimmune Pharmacology 13, no. 2 (March 17, 2018): 265–76. http://dx.doi.org/10.1007/s11481-018-9783-8.

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26

Cao, Cheng, Yanping Li, Yumei Leng, Ping Li, Qingjun Ma, and Donald Kufe. "Ubiquitination and degradation of the Arg tyrosine kinase is regulated by oxidative stress." Oncogene 24, no. 15 (February 7, 2005): 2433–40. http://dx.doi.org/10.1038/sj.onc.1208454.

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Parker, D., K. Ferreri, T. Nakajima, V. J. LaMorte, R. Evans, S. C. Koerber, C. Hoeger, and M. R. Montminy. "Phosphorylation of CREB at Ser-133 induces complex formation with CREB-binding protein via a direct mechanism." Molecular and Cellular Biology 16, no. 2 (February 1996): 694–703. http://dx.doi.org/10.1128/mcb.16.2.694.

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We have characterized a phosphoserine binding domain in the coactivator CREB-binding protein (CBP) which interacts with the protein kinase A-phosphorylated, and hence activated, form of the cyclic AMP-responsive factor CREB. The CREB binding domain, referred to as KIX, is alpha helical and binds to an unstructured kinase-inducible domain in CREB following phosphorylation of CREB at Ser-133. Phospho-Ser-133 forms direct contacts with residues in KIX, and these contacts are further stabilized by hydrophobic residues in the kinase-inducible domain which flank phospho-Ser-133. Like the src homology 2 (SH2) domains which bind phosphotyrosine-containing peptides, phosphoserine 133 appears to coordinate with a single arginine residue (Arg-600) in KIX which is conserved in the CBP-related protein P300. Since mutagenesis of Arg-600 to Gln severely reduces CREB-CBP complex formation, our results demonstrate that, as in the case of tyrosine kinase pathways, signal transduction through serine/threonine kinase pathways may also require protein interaction motifs which are capable of recognizing phosphorylated amino acids.

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Miura, O., N. Nakamura, FW Quelle, BA Witthuhn, JN Ihle, and N. Aoki. "Erythropoietin induces association of the JAK2 protein tyrosine kinase with the erythropoietin receptor in vivo." Blood 84, no. 5 (September 1, 1994): 1501–7. http://dx.doi.org/10.1182/blood.v84.5.1501.bloodjournal8451501.

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Protein tyrosine phosphorylation has been hypothesized to play a key role in the growth signaling induced by erythropoietin (Epo), although the Epo receptor (EpoR), a member of the cytokine receptor superfamily, lacks a tyrosine kinase domain. Recently, the JAK2 tyrosine kinase was shown to be activated on Epo stimulation and to bind to the cytoplasmic domain of EpoR in vitro. To further explore the mechanisms of activation of JAK2 in EpoR-mediated signal transduction, we assessed the conditions for association of JAK2 with EpoR in vivo. Epo stimulation rapidly induced association of JAK2 with the EpoR in an interleukin 3 (IL-3)-dependent cell line transfected with the wild-type EpoR. On Epo stimulation JAK2 also associated with a truncated mutant EpoR (H-mutant), which is mitogenetically active but not tyrosine phosphorylated, indicating that association does not require receptor phosphorylation and occurs in the membrane proximal region. However, association was not detected with mutant receptors inactivated by an internal deletion or a point mutation, Trp282 to Arg, in a membrane- proximal cytoplasmic region (PB or PM4 mutant, respectively). Immune complex kinase assays of anti-EpoR immunoprecipitates also revealed that activated JAK2 associates with the EpoR in Epo-stimulated cells. By this approach, association also occurred with the mitogenically active H mutant but not with the mitogenically inactive PB or PM4 mutants. In the immune complex kinases assays, EpoR, JAK2, and a 150-kD protein were phosphorylated on tyrosine. Taken together, the results further support the hypothesis that, on Epo stimulation, JAK2 associates with the membrane-proximal cytoplasmic region of the EpoR to be activated and induces tyrosine phosphorylation of cellular substrates, including the EpoR, to transduce a growth signal.

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Chen, Xiangjun, Xiaolin Sun, Wei Yang, Bing Yang, Xiaozhen Zhao, Shuting Chen, Lili He, et al. "An autoimmune disease variant of IgG1 modulates B cell activation and differentiation." Science 362, no. 6415 (October 4, 2018): 700–705. http://dx.doi.org/10.1126/science.aap9310.

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The maintenance of autoreactive B cells in a quiescent state is crucial for preventing autoimmunity. Here we identify a variant of human immunoglobulin G1 (IgG1) with a Gly396→Arg substitution (hIgG1-G396R), which positively correlates with systemic lupus erythematosus. In induced lupus models, murine homolog Gly390→Arg (G390R) knockin mice generate excessive numbers of plasma cells, leading to a burst of broad-spectrum autoantibodies. This enhanced production of antibodies is also observed in hapten-immunized G390R mice, as well as in influenza-vaccinated human G396R homozygous carriers. This variant potentiates the phosphorylation of the IgG1 immunoglobulin tail tyrosine (ITT) motif. This, in turn, alters the availability of phospho-ITT to trigger longer adaptor protein Grb2 dwell times in immunological synapses, leading to hyper–Grb2–Bruton’s tyrosine kinase (Btk) signaling upon antigen binding. Thus, the hIgG1-G396R variant is important for both lupus pathogenesis and antibody responses after vaccination.

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Genna, Alessandro, Stefanie Lapetina, Nikola Lukic, Shams Twafra, Tomer Meirson, Ved P. Sharma, John S. Condeelis, and Hava Gil-Henn. "Pyk2 and FAK differentially regulate invadopodia formation and function in breast cancer cells." Journal of Cell Biology 217, no. 1 (November 13, 2017): 375–95. http://dx.doi.org/10.1083/jcb.201702184.

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The nonreceptor tyrosine kinase Pyk2 is highly expressed in invasive breast cancer, but the mechanism by which it potentiates tumor cell invasiveness is unclear at present. Using high-throughput protein array screening and bioinformatic analysis, we identified cortactin as a novel substrate and interactor of proline-rich tyrosine kinase 2 (Pyk2). Pyk2 colocalizes with cortactin to invadopodia of invasive breast cancer cells, where it mediates epidermal growth factor–induced cortactin tyrosine phosphorylation both directly and indirectly via Src-mediated Abl-related gene (Arg) activation, leading to actin polymerization in invadopodia, extracellular matrix degradation, and tumor cell invasion. Both Pyk2 and the closely related focal adhesion kinase (FAK) regulate tumor cell invasion, albeit via distinct mechanisms. Although Pyk2 regulates tumor cell invasion by controlling invadopodium-mediated functions, FAK controls invasiveness of tumor cells by regulating focal adhesion–mediated motility. Collectively, our findings identify Pyk2 as a unique mediator of invadopodium formation and function and also provide a novel insight into the mechanisms by which Pyk2 mediates tumor cell invasion.

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Miura, O., N. Nakamura, FW Quelle, BA Witthuhn, JN Ihle, and N. Aoki. "Erythropoietin induces association of the JAK2 protein tyrosine kinase with the erythropoietin receptor in vivo." Blood 84, no. 5 (September 1, 1994): 1501–7. http://dx.doi.org/10.1182/blood.v84.5.1501.1501.

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Abstract Protein tyrosine phosphorylation has been hypothesized to play a key role in the growth signaling induced by erythropoietin (Epo), although the Epo receptor (EpoR), a member of the cytokine receptor superfamily, lacks a tyrosine kinase domain. Recently, the JAK2 tyrosine kinase was shown to be activated on Epo stimulation and to bind to the cytoplasmic domain of EpoR in vitro. To further explore the mechanisms of activation of JAK2 in EpoR-mediated signal transduction, we assessed the conditions for association of JAK2 with EpoR in vivo. Epo stimulation rapidly induced association of JAK2 with the EpoR in an interleukin 3 (IL-3)-dependent cell line transfected with the wild-type EpoR. On Epo stimulation JAK2 also associated with a truncated mutant EpoR (H-mutant), which is mitogenetically active but not tyrosine phosphorylated, indicating that association does not require receptor phosphorylation and occurs in the membrane proximal region. However, association was not detected with mutant receptors inactivated by an internal deletion or a point mutation, Trp282 to Arg, in a membrane- proximal cytoplasmic region (PB or PM4 mutant, respectively). Immune complex kinase assays of anti-EpoR immunoprecipitates also revealed that activated JAK2 associates with the EpoR in Epo-stimulated cells. By this approach, association also occurred with the mitogenically active H mutant but not with the mitogenically inactive PB or PM4 mutants. In the immune complex kinases assays, EpoR, JAK2, and a 150-kD protein were phosphorylated on tyrosine. Taken together, the results further support the hypothesis that, on Epo stimulation, JAK2 associates with the membrane-proximal cytoplasmic region of the EpoR to be activated and induces tyrosine phosphorylation of cellular substrates, including the EpoR, to transduce a growth signal.

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Beaty, Brian T., Ved P. Sharma, Jose J. Bravo-Cordero, Mark A. Simpson, Robert J. Eddy, Anthony J. Koleske, and John Condeelis. "β1 integrin regulates Arg to promote invadopodial maturation and matrix degradation." Molecular Biology of the Cell 24, no. 11 (June 2013): 1661–75. http://dx.doi.org/10.1091/mbc.e12-12-0908.

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β1 integrin has been shown to promote metastasis in a number of tumor models, including breast, ovarian, pancreatic, and skin cancer; however, the mechanism by which it does so is poorly understood. Invasive membrane protrusions called invadopodia are believed to facilitate extracellular matrix degradation and intravasation during metastasis. Previous work showed that β1 integrin localizes to invadopodia, but its role in regulating invadopodial function has not been well characterized. We find that β1 integrin is required for the formation of mature, degradation-competent invadopodia in both two- and three-dimensional matrices but is dispensable for invadopodium precursor formation in metastatic human breast cancer cells. β1 integrin is activated during invadopodium precursor maturation, and forced β1 integrin activation enhances the rate of invadopodial matrix proteolysis. Furthermore, β1 integrin interacts with the tyrosine kinase Arg and stimulates Arg-dependent phosphorylation of cortactin on tyrosine 421. Silencing β1 integrin with small interfering RNA completely abrogates Arg-dependent cortactin phosphorylation and cofilin-dependent barbed-end formation at invadopodia, leading to a significant decrease in the number and stability of mature invadopodia. These results describe a fundamental role for β1 integrin in controlling actin polymerization–dependent invadopodial maturation and matrix degradation in metastatic tumor cells.

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Jin, Hua, and Jean Y. J. Wang. "Abl Tyrosine Kinase Promotes Dorsal Ruffles but Restrains Lamellipodia Extension during Cell Spreading on Fibronectin." Molecular Biology of the Cell 18, no. 10 (October 2007): 4143–54. http://dx.doi.org/10.1091/mbc.e07-01-0085.

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The nonreceptor Abl tyrosine kinase stimulates F-actin microspikes and membrane ruffles in response to adhesion and growth factor signals. We show here that induced dimerization of Abl-FKBP, but not the kinase-defective AblKD-FKBP, inhibits cell spreading on fibronectin. Conversely, knockdown of cellular Abl by shRNA stimulates cell spreading. The Abl kinase inhibitor, imatinib, also stimulates cell spreading and its effect is overridden by the imatinib-resistant AblT315I. Expression of Abl but not AbkKD in Abl/Arg-deficient cells again inhibits spreading. Furthermore, Abl inhibits spreading of cells that express the activated Rac, RacV12, correlating with RacV12 localization to dorsal membrane protrusions. Ectopic expression of CrkII, a Rac activator that is inactivated by Abl-mediated tyrosine phosphorylation, antagonizes Abl-mediated dorsal membrane localization of RacV12. Ectopic expression of a dynamin-2 mutant, previously shown to induce Rac-GTP localization to the dorsal membrane, abolishes the stimulatory effect of imatinib on cell spreading. These results suggest that Abl tyrosine kinase, through CrkII phosphorylation and in collaboration with dynamin-2 can regulate the partitioning of Rac-GTP to favor dorsal ruffles during cell spreading. The Abl-dependent dorsal membrane localization of activated Rac explains its positive role in ruffling and negative role in cell spreading and migration.

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Liu, Weizhi, Stacey M. MacGrath, Anthony J. Koleske, and Titus J. Boggon. "Lysozyme contamination facilitates crystallization of a heterotrimeric cortactin–Arg–lysozyme complex." Acta Crystallographica Section F Structural Biology and Crystallization Communications 68, no. 2 (January 25, 2012): 154–58. http://dx.doi.org/10.1107/s1744309111056132.

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Crystallization of contaminating proteins is a frequently encountered problem for macromolecular crystallographers. In this study, an attempt was made to obtain a binary cocrystal structure of the SH3 domain of cortactin and a 17-residue peptide from the Arg nonreceptor tyrosine kinase encompassing a PxxPxxPxxP (PxxP1) motif. However, cocrystals could only be obtained in the presence of trace amounts of a contaminating protein. A structure solution obtained by molecular replacement followed byARP/wARPautomatic model building allowed a `sequence-by-crystallography' approach to discover that the contaminating protein was lysozyme. This 1.65 Å resolution crystal structure determination of a 1:1:1 heterotrimeric complex of Arg, cortactin and lysozyme thus provides an unusual `caveat emptor' warning of the dangers that underpurified proteins harbor for macromolecular crystallographers.

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Cao, Cheng, Xingping Ren, Surender Kharbanda, Anthony J. Koleske, K. V. S. Prasad, and Donald Kufe. "The ARG tyrosine kinase interacts with Siva-1 in the apoptotic response to oxidative stress." Journal of Biological Chemistry 287, no. 43 (October 19, 2012): 36527. http://dx.doi.org/10.1074/jbc.a112.100050.

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Oh-hora, Masatsugu, Masato Ogata, Yoshiko Mori, Masaaki Adachi, Kohzoh Imai, Atsushi Kosugi, and Toshiyuki Hamaoka. "Direct Suppression of TCR-Mediated Activation of Extracellular Signal-Regulated Kinase by Leukocyte Protein Tyrosine Phosphatase, a Tyrosine-Specific Phosphatase." Journal of Immunology 163, no. 3 (August 1, 1999): 1282–88. http://dx.doi.org/10.4049/jimmunol.163.3.1282.

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Abstract Leukocyte protein tyrosine phosphatase (LC-PTP)/hemopoietic PTP is a human cytoplasmic PTP that is predominantly expressed in the hemopoietic cells. Recently, it was reported that hemopoietic PTP inhibited TCR-mediated signal transduction. However, the precise mechanism of the inhibition was not identified. Here we report that extracellular signal-regulated kinase (ERK) is the direct target of LC-PTP. LC-PTP dephosphorylated ERK2 in vitro. Expression of wild-type LC-PTP in 293T cells suppressed the phosphorylation of ERK2 by a mutant MEK1, which was constitutively active regardless of upstream activation signals. No suppression of the phosphorylation was observed by LC-PTPCS, a catalytically inactive mutant. In Jurkat cells, LC-PTP suppressed the ERK and p38 mitogen-activated protein kinase cascades. LC-PTP and LC-PTPCS made complexes with ERK1, ERK2, and p38α, but not with the gain-of-function sevenmaker ERK2 mutant (D321N). A small deletion (aa 1–46) in the N-terminal portion of LC-PTP or Arg to Ala substitutions at aa 41 and 42 resulted in the loss of ERK binding activity. These LC-PTP mutants revealed little inhibition of the ERK cascade activated by TCR cross-linking. On the other hand, the wild-type LC-PTP did not suppress the phosphorylation of sevenmaker ERK2 mutant. Thus, the complex formation of LC-PTP with ERK is the essential mechanism for the suppression. Taken collectively, these results indicate that LC-PTP suppresses mitogen-activated protein kinase directly in vivo.

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Sato, Mizuho, Masahiro Maruoka, and Tatsuo Takeya. "Functional Mechanisms and Roles of Adaptor Proteins in Abl-Regulated Cytoskeletal Actin Dynamics." Journal of Signal Transduction 2012 (May 17, 2012): 1–13. http://dx.doi.org/10.1155/2012/414913.

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Abl is a nonreceptor tyrosine kinase and plays an essential role in the modeling and remodeling of F-actin by transducing extracellular signals. Abl and its paralog, Arg, are unique among the tyrosine kinase family in that they contain an unusual extended C-terminal half consisting of multiple functional domains. This structural characteristic may underlie the role of Abl as a mediator of upstream signals to downstream signaling machineries involved in actin dynamics. Indeed, a group of SH3-containing accessory proteins, or adaptor proteins, have been identified that bind to a proline-rich domain of the C-terminal portion of Abl and modulate its kinase activity, substrate recognition, and intracellular localization. Moreover, the existence of signaling cascade and biological outcomes unique to each adaptor protein has been demonstrated. In this paper, we summarize functional roles and mechanisms of adaptor proteins in Abl-regulated actin dynamics, mainly focusing on a family of adaptor proteins, Abi. The mechanism of Abl's activation and downstream signaling mediated by Abi is described in comparison with those by another adaptor protein, Crk.

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Claudio, Jaime O., Razi Khaja, Lihua Zhuang, Meenakshi Bali, Kamalanayani Sivananthan, Constantine C. Christopoulos, Rafael Fonseca, P. Leif Bergsagel, Stephen W. Scherer, and A. Keith Stewart. "Sequencing the Multiple Myeloma Kinome: Absence of Mutation in Known Malignancy-Associated Kinases." Blood 104, no. 11 (November 16, 2004): 783. http://dx.doi.org/10.1182/blood.v104.11.783.783.

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Abstract In approximately 50% of Multiple Myeloma (MM), translocation of non random genes into the IgH locus is believed to be the seminal event in the pathogenesis of the disease. Another 50% of cases are hyperdiploid and trisomic to certain autosomes, but do not harbor any translocation and thus are believed to have genetic alterations in unidentified loci. These observations, together with the finding of somatic mutations in FGFR3, N- and K-RAS, MYC, TP53 and CDKN2C/p18INK4C during the later stages of MM indicate that defective signaling pathways likely play a role in the progression of this malignancy. Of relevance then, in recent years recurrent mutations in kinases have frequently been implicated in malignancies including notably colon cancer and melanoma. We have therefore begun a comprehensive effort to sequence the tyrosine kinome for mutations and genetic polymorphisms in MM. Of particular interest are 90 receptor tyrosine kinases, 43 receptor tyrosine kinase-like, 5 receptor guanylate cyclase, and a lipid kinase. We report here results from our pilot high throughput exon scanning in 32 human MM cell lines which initially focused on 13 kinases known to be somatically mutated in human cancers. To date we have expanded this effort to assess 30 genes with sequence obtained which currently spans 80% coverage of the kinase domains of these genes. A total of 1.9 million bp have been sequenced across 235 exons. No recurrent mutations have been identified in the kinase domains of the cancer-associated genes: SRC, ILK1, KIT, GUCY2F, PDGFRA; in the genetic disorder-associated kinases: BTK, EPHA4, LAMA2, EPHB6, ACVR2; and in the mutation hot spots of frequently mutated cancer gene PIK3CA. A novel missense mutation is however identified upstream of the kinase domain of FGFR3 changing a Ser residue to Arg at codon 433. This residue, which is conserved across species and in FGFR1 and FGFR2, has not been reported in myeloma and in thanatophoric dysplasia, but the biological significance of this mutation is unknown. Several single nucleotide polymorphisms were identified in the coding regions of some of these kinases. Notably, synonymous polymorphisms in the kinase domains of EPHA4, PDGFRA3, KIT, MLK1, ILK1, NTRK3, FLT3, ABL1, FES, MLK4, and EGFR1 were identified that changed a codon but not the amino acid. More importantly, we identified non-synonymous amino acid variations in the kinase domains of EPHA4, GUCY2F, PTK2, and PIK3CA genes that are more likely to effect variability in the activity of these kinases. In summary, no recurrent kinase mutations of significance in Myeloma development or progression have yet been identified. Sequencing of the known cancer associated kinases in MGUS and hyperdiploid MM patients is now underway and our data set is being expanded to include all 139 kinases.

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Engler, D. A., M. R. Hauser, J. S. Cook, and S. K. Niyogi. "Aromaticity at position 37 in human epidermal growth factor is not obligatory for activity." Molecular and Cellular Biology 11, no. 5 (May 1991): 2425–31. http://dx.doi.org/10.1128/mcb.11.5.2425-2431.1991.

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The third disulfide loop (amino acids 33 to 42) of human epidermal growth factor (hEGF) encompasses the region of highest amino acid conservation among all of the EGF-like family of molecules. The importance of some of these highly conserved residues for the maintenance of biological activity, especially the aromatic amino acid tyrosine at position 37, has until now been considered essential on the basis of previous studies with the EGF-like molecule transforming growth factor alpha. Variants at the Tyr-37 position of hEGF were constructed by site-directed mutagenesis. The substituting amino acids were phenylalanine, histidine, serine, alanine, aspartic acid, arginine, and glycine. The variants were tested for their ability to competitively displace native [125I]hEGF from its receptor and to stimulate the protein-tyrosine kinase activity of the receptor; the order of efficacy of substituting amino acids was Phe greater than His greater than Ser greater than Ala greater than Asp greater than Arg greater than Gly in both assays. All were effective, with no or only moderate reduction in potency, in stimulating the incorporation of [3H]thymidine into acid-insoluble material of quiescent mouse A31 cells. Only Tyr-37----Ala, Tyr-37----Arg and Tyr-37----Gly were slightly less potent in the cell assay. Thus, neither tyrosine nor another aromatic amino acid at position 37 in hEGF is essential for full biological activity.

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40

Engler, D. A., M. R. Hauser, J. S. Cook, and S. K. Niyogi. "Aromaticity at position 37 in human epidermal growth factor is not obligatory for activity." Molecular and Cellular Biology 11, no. 5 (May 1991): 2425–31. http://dx.doi.org/10.1128/mcb.11.5.2425.

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The third disulfide loop (amino acids 33 to 42) of human epidermal growth factor (hEGF) encompasses the region of highest amino acid conservation among all of the EGF-like family of molecules. The importance of some of these highly conserved residues for the maintenance of biological activity, especially the aromatic amino acid tyrosine at position 37, has until now been considered essential on the basis of previous studies with the EGF-like molecule transforming growth factor alpha. Variants at the Tyr-37 position of hEGF were constructed by site-directed mutagenesis. The substituting amino acids were phenylalanine, histidine, serine, alanine, aspartic acid, arginine, and glycine. The variants were tested for their ability to competitively displace native [125I]hEGF from its receptor and to stimulate the protein-tyrosine kinase activity of the receptor; the order of efficacy of substituting amino acids was Phe greater than His greater than Ser greater than Ala greater than Asp greater than Arg greater than Gly in both assays. All were effective, with no or only moderate reduction in potency, in stimulating the incorporation of [3H]thymidine into acid-insoluble material of quiescent mouse A31 cells. Only Tyr-37----Ala, Tyr-37----Arg and Tyr-37----Gly were slightly less potent in the cell assay. Thus, neither tyrosine nor another aromatic amino acid at position 37 in hEGF is essential for full biological activity.

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41

Torsello, Barbara, Cristina Bianchi, Chiara Meregalli, Vitalba Di Stefano, Lara Invernizzi, Sofia De Marco, Giorgio Bovo, et al. "Arg tyrosine kinase modulates TGF-β1 production in human renal tubular cells under high-glucose conditions." Journal of Cell Science 129, no. 15 (June 13, 2016): 2925–36. http://dx.doi.org/10.1242/jcs.183640.

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Shimizu, Akio, Akiko Mammoto, Joseph E. Italiano, Elke Pravda, Andrew C. Dudley, Donald E. Ingber, and Michael Klagsbrun. "ABL2/ARG Tyrosine Kinase Mediates SEMA3F-induced RhoA Inactivation and Cytoskeleton Collapse in Human Glioma Cells." Journal of Biological Chemistry 283, no. 40 (July 25, 2008): 27230–38. http://dx.doi.org/10.1074/jbc.m804520200.

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43

Somogyi, L., Z. Lasić, S. Vukičević, and H. Banfić. "Collagen type IV stimulates an increase in intracellular Ca2+ in pancreatic acinar cells via activation of phospholipase C." Biochemical Journal 299, no. 3 (May 1, 1994): 603–11. http://dx.doi.org/10.1042/bj2990603.

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Intracellular Ca2+ responses to extracellular matrix molecules were studied in suspensions of pancreatic acinar cells loaded with Fura-2. Collagen type I, laminin, fibrinogen and fibronectin were unable to raise cytosolic free Ca2+ concentration ([Ca2+]i), whereas collagen type IV, at concentrations from 5 to 50 micrograms/ml, significantly increased it. The effect of collagen type IV was not due to possible contamination with type-I transforming growth factor beta or plasminogen, as neither of these agents was able to increase [Ca2+]i. Using highly specific mass assays, concentrations of inositol lipids, 1,2-diacylglycerol (DAG) and Ins(1,4,5) P3 were measured in pancreatic acinar cells stimulated with collagen type IV. A decrease in the concentrations of PtdIns(4,5) P2 and PtdIns4 P with a concomitant increase in the concentrations of DAG and InsP3 mass were observed, showing that collagen type IV increases [Ca2+]i by activation of phospholipase C. The observed [Ca2+]i signals had two components, the first resulting from Ca2+ release from the intracellular stores, and the second resulting from Ca2+ flux from the extracellular medium through the verapamil-insensitive channels. A tyrosine kinase inhibitor (tyrphostine) was able to block inositol lipid signalling caused by collagen type IV, which together with the insensitivity of this pathway to cholera toxin and pertussis toxin or to preactivation of protein kinase C, the longer duration of the increase in [Ca2+]i and a longer lag period needed for observation of increases in DAG and InsP3 concentration with collagen type IV than with carbachol (50 mM) suggest that activation of phospholipase C by collagen type IV is caused by tyrosine kinase activation. Inositol lipid signalling and increases in [Ca2+]i were also observed with Arg-Gly-Asp (RGD)-containing peptide but not with Arg-Asp-Gly (RDG)-containing peptide. Collagen type IV and RGD-containing peptide, but not carbachol, competed in increasing [Ca2+]i and DAG concentration, suggesting that the binding site of collagen type IV responsible for phospholipase C activation contains the RGD sequence. Together the present results suggest that, in pancreatic acinar cells, RGD sequence(s) within collagen type IV molecules cause activation of tyrosine kinase, probably through one of the integrin receptors, which then stimulates phospholipase C and increases [Ca2+]i.

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Bradley, William D., Samuel E. Hernández, Jeffrey Settleman, and Anthony J. Koleske. "Integrin Signaling through Arg Activates p190RhoGAP by Promoting Its Binding to p120RasGAP and Recruitment to the Membrane." Molecular Biology of the Cell 17, no. 11 (November 2006): 4827–36. http://dx.doi.org/10.1091/mbc.e06-02-0132.

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The Rho family GTPases RhoA (Rho), Rac1, and Cdc42 are essential effectors of integrin-mediated cell attachment and spreading. Rho activity, which promotes formation of focal adhesions and actin stress fibers, is inhibited upon initial cell attachment to allow sampling of the new adhesive environment. The Abl-related gene (Arg) tyrosine kinase mediates adhesion-dependent inhibition of Rho through phosphorylation and activation of the Rho inhibitor p190RhoGAP-A (p190). p190 phosphorylation promotes its binding to p120RasGAP (p120). Here, we elucidate the mechanism by which p120 binding regulates p190 activation after adhesion. We show that p190 requires its p120-binding domain to undergo Arg-dependent activation in vivo. However, p120 binding does not activate p190RhoGAP activity in vitro. Instead, activation of p190 requires recruitment to the cell periphery. Integrin-mediated adhesion promotes relocalization of p190 and p120 to the cell periphery in wild-type fibroblasts, but not in arg−/− fibroblasts. A dominant-negative p120 fragment blocks p190:p120 complex formation, prevents activation of p190 by adhesion, and disrupts the adhesion-dependent recruitment of p190 to the cell periphery. Our results demonstrate that integrin signaling through Arg activates p190 by promoting its association with p120, resulting in recruitment of p190 to the cell periphery where it inhibits Rho.

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Madden, Jane A., and Norbert J. T. Christman. "Integrin signaling, free radicals, and tyrosine kinase mediate flow constriction in isolated cerebral arteries." American Journal of Physiology-Heart and Circulatory Physiology 277, no. 6 (December 1, 1999): H2264—H2271. http://dx.doi.org/10.1152/ajpheart.1999.277.6.h2264.

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Isolated, cannulated, and pressurized (100 mmHg) middle cerebral arteries from adult cats were perfused intraluminally at rates from 0 to 4 ml/min with heated and gassed physiological saline solution. An electronic system held pressure constant by changing outflow resistance. The arteries constricted 18.1 ± 0.95% in response to flow and depolarized from −54 ± 0.51 to −40 ± 1.26 mV ( P < 0.05). Constriction was independent of a functional endothelium but was eliminated by superoxide dismutase or tyrosine kinase inhibitors. Luminal perfusion with a synthetic extracellular matrix Arg-Gly-ASP (RGD) peptide that binds with integrin significantly reduced constriction to flow. Neither reducing intraluminal pressure nor increasing tone or shear stresses altered constriction to flow. Flow-induced constriction did not impede the ability of the arteries to dilate to hypercapnia, and inhibiting flow-induced constriction did not alter contractile responses to other agonists. These data suggest that, in vitro, middle cerebral arteries constrict to flow through a mechanism involving free radicals and tyrosine kinase and that flow shear stresses resulting in constriction are transduced by integrin signaling.

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46

Kim, Y. J., K. E. Pollok, Z. Zhou, A. Shaw, J. B. Bohlen, M. Fraser, and B. S. Kwon. "Novel T cell antigen 4-1BB associates with the protein tyrosine kinase p56lck1." Journal of Immunology 151, no. 3 (August 1, 1993): 1255–62. http://dx.doi.org/10.4049/jimmunol.151.3.1255.

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Abstract 4-1BB is a 30-kDa inducible T cell Ag, and is expressed predominantly as a 55-kDa dimer on both CD4+ and CD8+ T lymphocytes. The cytoplasmic tail of 4-1BB contains the sequence Cys-Arg-Cys-Pro, which is similar to the sequence Cys-X-Cys-Pro, which mediates the binding of the CD4 and CD8 molecules to the protein tyrosine kinase p56lck. An anti-4-1BB mAb, 53A2, was used to determine whether 4-1BB may associate with p56lck. The 53A2 mAb specifically recognized 4-1BB on a CD8+ T cell line, CTLL-2, and coimmunoprecipitated a 56-kDa protein along with 4-1BB. Peptide mapping indicated that the 56-kDa phosphoprotein was identical to p56lck. The coimmunoprecipitation of p56lck with 4-1BB also occurred in nonlymphoid cells such as insect (Sf-21) and HeLa cells when the two recombinant proteins were coexpressed. Analysis of mutant p56lck recombinant proteins showed that two cysteine residues critical for p56lck-CD4 (or -CD8) complex formation are also required for the p56lck-4-1BB interaction. These studies establish that 4-1BB physically associates with p56lck.

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47

Grundler, Rebekka, Christian Thiede, Cornelius Miething, Christine Steudel, Christian Peschel, and Justus Duyster. "Sensitivity toward tyrosine kinase inhibitors varies between different activating mutations of the FLT3 receptor." Blood 102, no. 2 (July 15, 2003): 646–51. http://dx.doi.org/10.1182/blood-2002-11-3441.

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AbstractActivating mutations of FLT3 have been detected in patients with acute myeloid leukemia (AML). Two distinct types of FLT3 mutations are most common: internal tandem duplication (ITD) of sequences coding for the juxtamembrane domain and point mutations at codon 835 (Asp835) within the kinase domain. Both types of mutations constitutively activate the tyrosine kinase activity of FLT3 in experimental systems and result in factor-independent proliferation of Ba/F3 and 32D cells. Recently, novel mutations within the activation loop were identified in patients with AML: deletion of isoleucine 836 (Ile836del) and an exchange of isoleucine 836 to methionine plus an arginine insertion (Ile836Met+Arg). To examine whether the Ile836 mutations result in constitutive activation of the FLT3 receptor, we introduced both mutant FLT3 cDNAs transiently into HEK 293 cells. Both mutant FLT3 receptors were constitutively autophosphorylated in the absence of ligand and kinase activity led to constitutive activation of downstream signaling cascades as determined by activation of the STAT5 (signal transducer and activator of transcription 5) pathway. When stably expressed in the growth factor–dependent cell lines Ba/F3 and 32D, both deletion and insertion mutants led to factor-independent proliferation, indicating that both mutants have transforming capabilities. We then examined the sensitivity of the FLT3 ITD, FLT3 Asp835Tyr, and the novel FLT3 receptor mutants toward the kinase inhibitors AG1296, PKC412, and SU5614. We show that these FLT3 kinase inhibitors have distinct inhibitory potencies against different activating FLT3 receptor mutants. These results suggest that it may be useful to determine the exact kind of FLT3 mutation when applying receptor kinase inhibitors in clinical trials.

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48

Torsello, Barbara, Cristina Bianchi, Chiara Meregalli, Vitalba Di Stefano, Lara Invernizzi, Sofia De Marco, Giorgio Bovo, et al. "Retraction: Arg tyrosine kinase modulates TGF-β1 production in human renal tubular cells under high-glucose conditions." Journal of Cell Science 133, no. 20 (October 15, 2020): jcs254847. http://dx.doi.org/10.1242/jcs.254847.

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49

Zhang, Hao, Lingwei Sun, Ziyu Wang, Mingtian Deng, Haitao Nie, Guomin Zhang, Tiewei Ma, and Feng Wang. "N-carbamylglutamate and L-arginine improved maternal and placental development in underfed ewes." Reproduction 151, no. 6 (June 2016): 623–35. http://dx.doi.org/10.1530/rep-16-0067.

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AbstractThe objectives of this study were to determine how dietary supplementation ofN-carbamylglutamate (NCG) and rumen-protected L-arginine (RP-Arg) in nutrient-restricted pregnant Hu sheep would affect (1) maternal endocrine status; (2) maternal, fetal, and placental antioxidation capability; and (3) placental development. From day 35 to day 110 of gestation, 32 Hu ewes carrying twin fetuses were allocated randomly into four groups: 100% of NRC-recommended nutrient requirements, 50% of NRC recommendations, 50% of NRC recommendations supplemented with 20g/day RP-Arg, and 50% of NRC recommendations supplemented with 5g/day NCG product. The results showed that in maternal and fetal plasma and placentomes, the activities of total antioxidant capacity and superoxide dismutase were increased (P<0.05); however, the activity of glutathione peroxidase and the concentration of maleic dialdehyde were decreased (P<0.05) in both NCG- and RP-Arg-treated underfed ewes. The mRNA expression of vascular endothelial growth factor and Fms-like tyrosine kinase 1 was increased (P<0.05) in 50% NRC ewes than in 100% NRC ewes, and had no effect (P>0.05) in both NCG- and RP-Arg-treated underfed ewes. A supplement of RP-Arg and NCG reduced (P<0.05) the concentrations of progesterone, cortisol, and estradiol-17β; had no effect on T4/T3; and improved (P<0.05) the concentrations of leptin, insulin-like growth factor 1, tri-iodothyronine (T3), and thyroxine (T4) in serum from underfed ewes. These results indicate that dietary supplementation of NCG and RP-Arg in underfed ewes could influence maternal endocrine status, improve the maternal–fetal–placental antioxidation capability, and promote fetal and placental development during early-to-late gestation.

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50

Dewar, Andrea L., Antony C. Cambareri, Andrew C. W. Zannettino, Bernadette L. Miller, Kathleen V. Doherty, Timothy P. Hughes, and A. Bruce Lyons. "Macrophage colony-stimulating factor receptor c-fms is a novel target of imatinib." Blood 105, no. 8 (April 15, 2005): 3127–32. http://dx.doi.org/10.1182/blood-2004-10-3967.

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AbstractImatinib is a tyrosine kinase inhibitor that suppresses the growth of bcr-abl–expressing chronic myeloid leukemia (CML) progenitor cells by blockade of the adenosine triphosphate (ATP)–binding site of the kinase domain of bcr-abl. Imatinib also inhibits the c-abl, platelet-derived growth factor (PDGF) receptor, abl-related gene (ARG) and stem-cell factor (SCF) receptor tyrosine kinases, and has been used clinically to inhibit the growth of malignant cells in patients with CML and gastrointestinal stromal tumors (GISTs). Although initially considered to have minimal effects of normal hematopoiesis, recent studies show that imatinib also inhibits the growth of some nonmalignant hematopoietic cells, including monocyte/macrophages. This inhibition could not be attributed to the known activity profile of imatinib. Here, we demonstrate for the first time that imatinib targets the macrophage colony-stimulating factor (M-CSF) receptor c-fms. Phosphorylation of c-fms was inhibited by therapeutic concentrations of imatinib, and this was not due to down-regulation in c-fms expression. Imatinib was also found to inhibit M-CSF–induced proliferation of a cytokine–dependent cell line, further supporting the hypothesis that imatinib affects the growth and development of monocyte and/or macrophages through inhibition of c-fms signaling. Importantly, these results identify an additional biologic target to those already defined for imatinib. Imatinib should now be assessed for activity in diseases where c-fms activation is implicated, including breast and ovarian cancer and inflammatory conditions.

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Journal articles on the topic 'Arg tyrosine kinase'

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