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1
Buxade, Maria. "The Mnks: MAP kinase-interacting kinases (MAP kinase signal-integrating kinases)." Frontiers in Bioscience Volume, no. 13 (2008): 5359. http://dx.doi.org/10.2741/3086.
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Hurley, Rebecca L., Kristin A. Anderson, Jeanne M. Franzone, Bruce E. Kemp, Anthony R. Means, and Lee A. Witters. "The Ca2+/Calmodulin-dependent Protein Kinase Kinases Are AMP-activated Protein Kinase Kinases." Journal of Biological Chemistry 280, no. 32 (June 24, 2005): 29060–66. http://dx.doi.org/10.1074/jbc.m503824200.
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Songyang, Z., K. P. Lu, Y. T. Kwon, L. H. Tsai, O. Filhol, C. Cochet, D. A. Brickey, et al. "A structural basis for substrate specificities of protein Ser/Thr kinases: primary sequence preference of casein kinases I and II, NIMA, phosphorylase kinase, calmodulin-dependent kinase II, CDK5, and Erk1." Molecular and Cellular Biology 16, no. 11 (November 1996): 6486–93. http://dx.doi.org/10.1128/mcb.16.11.6486.
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We have developed a method to study the primary sequence specificities of protein kinases by using an oriented degenerate peptide library. We report here the substrate specificities of eight protein Ser/Thr kinases. All of the kinases studied selected distinct optimal substrates. The identified substrate specificities of these kinases, together with known crystal structures of protein kinase A, CDK2, Erk2, twitchin, and casein kinase I, provide a structural basis for the substrate recognition of protein Ser/Thr kinases. In particular, the specific selection of amino acids at the +1 and -3 positions to the substrate serine/threonine can be rationalized on the basis of sequences of protein kinases. The identification of optimal peptide substrates of CDK5, casein kinases I and II, NIMA, calmodulin-dependent kinases, Erk1, and phosphorylase kinase makes it possible to predict the potential in vivo targets of these kinases.
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Moens, Ugo, and Sergiy Kostenko. "Structure and function of MK5/PRAK: the loner among the mitogen-activated protein kinase-activated protein kinases." Biological Chemistry 394, no. 9 (September 1, 2013): 1115–32. http://dx.doi.org/10.1515/hsz-2013-0149.
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Abstract Mitogen-activated protein kinase (MAPK) pathways are important signal transduction pathways that control pivotal cellular processes including proliferation, differentiation, survival, apoptosis, gene regulation, and motility. MAPK pathways consist of a relay of consecutive phosphorylation events exerted by MAPK kinase kinases, MAPK kinases, and MAPKs. Conventional MAPKs are characterized by a conserved Thr-X-Tyr motif in the activation loop of the kinase domain, while atypical MAPKs lack this motif and do not seem to be organized into the classical three-tiered kinase cascade. One functional group of conventional and atypical MAPK substrates consists of protein kinases known as MAPK-activated protein kinases. Eleven mammalian MAPK-activated protein kinases have been identified, and they are divided into five subgroups: the ribosomal-S6-kinases RSK1-4, the MAPK-interacting kinases MNK1 and 2, the mitogen- and stress-activated kinases MSK1 and 2, the MAPK-activated protein kinases MK2 and 3, and the MAPK-activated protein kinase MK5 (also referred to as PRAK). MK5/PRAK is the only MAPK-activated protein kinase that is a substrate for both conventional and atypical MAPK, while all other MAPKAPKs are exclusively phosphorylated by conventional MAPKs. This review focuses on the structure, activation, substrates, functions, and possible implications of MK5/PRAK in malignant and nonmalignant diseases.
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LANG, Mark L., Yih-Wen CHEN, Li SHEN, Hong GAO, Gillian A. LANG, Terri K. WADE, and William F. WADE. "IgA Fc receptor (FcαR) cross-linking recruits tyrosine kinases, phosphoinositide kinases and serine/threonine kinases to glycolipid rafts." Biochemical Journal 364, no. 2 (June 1, 2002): 517–25. http://dx.doi.org/10.1042/bj20011696.
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The human IgA Fc receptor (FcαR, CD89) triggers several important physiological functions, including phagocytosis, NADPH oxidase activation and antigen presentation. Efforts are underway to delineate FcαR signal-transduction pathways that control these functions. In a previous study, we demonstrated that cross-linking of FcαR increased its partitioning into membrane glycolipid rafts and was accompanied by γ-chain-dependent recruitment and phosphorylation of the tyrosine kinases Lck/Yes-related novel protein tyrosine kinase (Lyn) and Bruton's tyrosine kinase (Btk). Here we have performed a more extensive characterization of signalling effectors recruited to rafts on FcαR cross-linking. We demonstrate that in addition to tyrosine kinases Lyn and Btk, FcαR cross-linking also recruits B-lymphocyte kinase (Blk) and spleen tyrosine kinase (Syk) to rafts. We show recruitment of phosphoinositide kinases, including 3-phosphoinositide 3-kinase and phospholipase Cγ2, and serine/threonine kinases such as protein kinase C (PKC) α, PKC∊, and protein kinase B (PKB) α. This suggests that lipid rafts serve as sites for FcαR-triggered recruitment of multiple classes of signalling effectors. We further demonstrate that tyrosine kinases and PKCα have a sustained association with rafts, whereas phosphoinositide 3-kinase and its downstream effectors have a transient association with rafts. This is consistent with temporally regulated divergence of FcαR signalling pathways in rafts. Furthermore, we suggest the spatial separation of signalling effectors by transport of phosphoinositide 3-kinase, phosphoinositide-dependent kinase 1, PKBα and PKC∊ to endocytic compartments containing internalized FcαR.
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Ibrahim, Samar H., Petra Hirsova, Harmeet Malhi, and Gregory J. Gores. "Nonalcoholic Steatohepatitis Promoting Kinases." Seminars in Liver Disease 40, no. 04 (June 11, 2020): 346–57. http://dx.doi.org/10.1055/s-0040-1713115.
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AbstractNonalcoholic hepatitis (NASH) is the progressive inflammatory form of nonalcoholic fatty liver disease. Although the mechanisms of hepatic inflammation in NASH remain incompletely understood, emerging literature implicates the proinflammatory environment created by toxic lipid-induced hepatocyte injury, termed lipotoxicity. Interestingly, numerous NASH-promoting kinases in hepatocytes, immune cells, and adipocytes are activated by the lipotoxic insult associated with obesity. In the current review, we discuss recent advances in NASH-promoting kinases as disease mediators and therapeutic targets. The focus of the review is mainly on the mitogen-activated protein kinases including mixed lineage kinase 3, apoptosis signal-regulating kinase 1, c-Jun N-terminal kinase, and p38 MAPK; the endoplasmic reticulum (ER) stress kinases protein kinase RNA-like ER kinase and inositol-requiring protein-1α; as well as the Rho-associated protein kinase 1. We also discuss various pharmacological agents targeting these stress kinases in NASH that are under different phases of development.
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Atkinson, Eleanor L., Jessica Iegre, Paul D. Brear, Elizabeth A. Zhabina, Marko Hyvönen, and David R. Spring. "Downfalls of Chemical Probes Acting at the Kinase ATP-Site: CK2 as a Case Study." Molecules 26, no. 7 (March 31, 2021): 1977. http://dx.doi.org/10.3390/molecules26071977.
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Protein kinases are a large class of enzymes with numerous biological roles and many have been implicated in a vast array of diseases, including cancer and the novel coronavirus infection COVID-19. Thus, the development of chemical probes to selectively target each kinase is of great interest. Inhibition of protein kinases with ATP-competitive inhibitors has historically been the most widely used method. However, due to the highly conserved structures of ATP-sites, the identification of truly selective chemical probes is challenging. In this review, we use the Ser/Thr kinase CK2 as an example to highlight the historical challenges in effective and selective chemical probe development, alongside recent advances in the field and alternative strategies aiming to overcome these problems. The methods utilised for CK2 can be applied to an array of protein kinases to aid in the discovery of chemical probes to further understand each kinase’s biology, with wide-reaching implications for drug development.
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Grishin, Andrey, Maia Cherney, Tara Condos, Kathryn Barber, Deborah Anderson, Sadhna Phanse, Mohan Babu, Gary Shaw, and Miroslaw Cygler. "Bacterial Effector Kinases." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C428. http://dx.doi.org/10.1107/s2053273314095710.
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Protein phosphorylation is one of the main signaling mechanisms in eukaryotic cells. Not surprisingly, pathogenic adopted this mechanism to interfere with signaling processes in the host cell. To this end pathogens evolved kinases that, in addition to other bacterial effector proteins, are injected into the host cell via a syringe-like type 3 (T3SS) or type 4 (T4SS) secretion systems. Kinases NleH1 and NleH2 from pathogenic E. coli, OspG from Shigella, SteC and SboH from Salmonella, LegK1-4 from Legionella and YspK and YpkA from Yersinia represent currently known effector kinases. Some of these kinases were likely derived from eukaryotes via horizontal gene transfer (SteC, LegK1-4, YpkA). Other kinases (NleH, OspG, SboH and YspK) have been so far identified only in the pathogenic bacteria. The structures of NleH and OspG proved that these kinases, which are half the size of an average human kinase, contain only a core kinase fold. These kinases lack the main regulatory element – the activation loop. The structure of NleH suggests that it has no activation mechanism since the apo-kinase domain adopts an active conformation and no change is observed on nucleotide binding. The OspG kinase, which also contains only the core kinase fold, is stimulated by its binding partner, the ubiquitin-conjugating enzyme E2-ubiquitin complex. The structure of OspG:UbcH7-Ub complex shows that OspG binds the E2 and ubiquitin (Ub) at two distinct sites on its surface. In this complex the OspG active site is unobstructed and primed for catalysis. However the mechanism of OspG activation remains presently unknown. Both NleH and OspG were found to inhibit the NF-kB pathway, however the substrates forOspG and NleH kinase activities are not yet known.
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Yamboliev, Ilia A., Kevin M. Wiesmann, Cherie A. Singer, Jason C. Hedges, and William T. Gerthoffer. "Phosphatidylinositol 3-kinases regulate ERK and p38 MAP kinases in canine colonic smooth muscle." American Journal of Physiology-Cell Physiology 279, no. 2 (August 1, 2000): C352—C360. http://dx.doi.org/10.1152/ajpcell.2000.279.2.c352.
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In canine colon, M2/M3 muscarinic receptors are coupled to extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein (MAP) kinases. We tested the hypothesis that this coupling is mediated by enzymes of the phosphatidylinositol (PI) 3-kinase family. RT-PCR and Western blotting demonstrated expression of two isoforms, PI 3-kinase-α and PI 3-kinase-γ. Muscarinic stimulation of intact muscle strips (10 μM ACh) activated PI 3-kinase-γ, ERK and p38 MAP kinases, and MAP kinase-activated protein kinase-2, whereas PI 3-kinase-α activation was not detected. Wortmannin (25 μM) abolished the activation of PI 3-kinase-γ, ERK, and p38 MAP kinases. MAP kinase inhibition was a PI 3-kinase-γ-specific effect, since wortmannin did not inhibit recombinant activated murine ERK2 MAP kinase, protein kinase C, Raf-1, or MAP kinase kinase. In cultured muscle cells, newborn calf serum (3%) activated PI 3-kinase-α and PI 3-kinase-γ isoforms, ERK and p38 MAP kinases, and stimulated chemotactic cell migration. Using wortmannin and LY-294002 to inhibit PI 3-kinase activity and PD-098059 and SB-203580 to inhibit ERK and p38 MAP kinases, we established that these enzymes are functionally important for regulation of chemotactic migration of colonic myocytes.
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Sclafani, Robert A. "Cyclin dependent kinase activating kinases." Current Opinion in Cell Biology 8, no. 6 (December 1996): 788–94. http://dx.doi.org/10.1016/s0955-0674(96)80079-2.
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Abraham, Robert T. "Phosphatidylinositol 3-kinase related kinases." Current Opinion in Immunology 8, no. 3 (June 1996): 412–18. http://dx.doi.org/10.1016/s0952-7915(96)80132-4.
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Wille, Christoph, Thomas Seufferlein, and Tim Eiseler. "Protein Kinase D family kinases." BioArchitecture 4, no. 3 (March 12, 2014): 111–15. http://dx.doi.org/10.4161/bioa.29273.
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Archambault, Vincent, and Mar Carmena. "Polo-like kinase-activating kinases." Cell Cycle 11, no. 8 (April 15, 2012): 1490–95. http://dx.doi.org/10.4161/cc.19724.
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Lebakken, Connie S., Hee Chol Kang, and Kurt W. Vogel. "A Fluorescence Lifetime–Based Binding Assay to Characterize Kinase Inhibitors." Journal of Biomolecular Screening 12, no. 6 (May 21, 2007): 828–41. http://dx.doi.org/10.1177/1087057107304480.
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The authors present a fluorescence lifetime—based kinase binding assay that identifies and characterizes compounds that bind to the adenosine triphosphate (ATP)—binding pocket of a range of tyrosine and serine/threonine kinases. The assay is based on displacement of an Alexa Fluor® 647 conjugate of staurosporine from the ATP-binding site of a kinase, which is detected by a change in the fluorescence lifetime of the probe between the free (displaced) and kinase-bound states. The authors screened 257 kinases for specific binding and displacement of the Alexa Fluor® 647-staurosporine probe and found that approximately half of the kinases tested could potentially be assayed with this method. They present inhibitor binding data against 4 selected serine/threonine kinases and 4 selected tyrosine kinases, using 6 commonly used kinase inhibitors. Two of these kinases were chosen for further studies, in which inhibitor binding data were compared to inhibition of kinase activity using 2 separate activity assay formats. Rank-order potencies of compounds were similar, but not identical, between the binding and activity assays. It was postulated that these differences could be caused by the fact that the assays are measuring distinct phenomena, namely, activity versus binding, and in a purified recombinant kinase preparation, there can exist a mixture of active and nonactivated kinases. To explore this possibility, the authors compared binding affinity for the probe using 2 kinases in their respective nonactivated and activated (phosphorylated) forms and found a kinase-dependent difference between the 2 forms. This assay format therefore represents a simple method for the identification and characterization of small-molecule kinase inhibitors that may be useful in screening a wide range of kinases and may be useful in identifying small molecules that bind to kinases in their active or nonactivated states. ( Journal of Biomolecular Screening 2007:828-841)
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Sunderhaus, Allison, Ramsha Imran, Elanzou Enoh, Adesola Adedeji, Taiye Obafemi, and May H. Abdel Aziz. "Comparative expression of soluble, active human kinases in specialized bacterial strains." PLOS ONE 17, no. 4 (April 19, 2022): e0267226. http://dx.doi.org/10.1371/journal.pone.0267226.
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Kinases act as molecular switches for cellular functions and are involved in multiple human pathogeneses, most notably cancer. There is a continuous need for soluble and active kinases for in-vitro drug discovery and structural biology purposes. Kinases remain challenging to express using Escherichia coli, the most widely utilized host for heterologous expression. In this work, four bacterial strains, BL21 (DE3), BL21 (DE3) pLysS, Rosetta, and Arctic Express, were chosen for parallel expression trials along with BL21 (DE3) complemented with folding chaperones DnaJ/K and GroEL/ES to compare their performance in producing soluble and active human kinases. Three representative diverse kinases were studied, Epidermal Growth Factor Receptor kinase domain, Aurora Kinase A kinase domain, and Mitogen-activated protein Kinase Kinase. The genes encoding the kinases were subcloned into pET15b bacterial plasmid and transformed into the bacterial strains. Soluble kinase expression was tested using different IPTG concentrations (1–0.05 mM) at varying temperatures (37°C– 10°C) and induction times (3–24 hours). The optimum conditions for each kinase in all strains were then used for 1L large scale cultures from which each kinase was purified to compare yield, purity, oligomerization status, and activity. Although using specialized strains achieved improvements in yield and/or activity for the three kinases, none of the tested strains was universally superior, highlighting the individuality in kinase expression.
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Creeden, Justin F., Khaled Alganem, Ali S. Imami, F. Charles Brunicardi, Shi-He Liu, Rammohan Shukla, Tushar Tomar, Faris Naji, and Robert E. McCullumsmith. "Kinome Array Profiling of Patient-Derived Pancreatic Ductal Adenocarcinoma Identifies Differentially Active Protein Tyrosine Kinases." International Journal of Molecular Sciences 21, no. 22 (November 17, 2020): 8679. http://dx.doi.org/10.3390/ijms21228679.
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Pancreatic cancer remains one of the most difficult malignancies to treat. Minimal improvements in patient outcomes and persistently abysmal patient survival rates underscore the great need for new treatment strategies. Currently, there is intense interest in therapeutic strategies that target tyrosine protein kinases. Here, we employed kinome arrays and bioinformatic pipelines capable of identifying differentially active protein tyrosine kinases in different patient-derived pancreatic ductal adenocarcinoma (PDAC) cell lines and wild-type pancreatic tissue to investigate the unique kinomic networks of PDAC samples and posit novel target kinases for pancreatic cancer therapy. Consistent with previously described reports, the resultant peptide-based kinome array profiles identified increased protein tyrosine kinase activity in pancreatic cancer for the following kinases: epidermal growth factor receptor (EGFR), fms related receptor tyrosine kinase 4/vascular endothelial growth factor receptor 3 (FLT4/VEGFR-3), insulin receptor (INSR), ephrin receptor A2 (EPHA2), platelet derived growth factor receptor alpha (PDGFRA), SRC proto-oncogene kinase (SRC), and tyrosine kinase non receptor 2 (TNK2). Furthermore, this study identified increased activity for protein tyrosine kinases with limited prior evidence of differential activity in pancreatic cancer. These protein tyrosine kinases include B lymphoid kinase (BLK), Fyn-related kinase (FRK), Lck/Yes-related novel kinase (LYN), FYN proto-oncogene kinase (FYN), lymphocyte cell-specific kinase (LCK), tec protein kinase (TEC), hemopoietic cell kinase (HCK), ABL proto-oncogene 2 kinase (ABL2), discoidin domain receptor 1 kinase (DDR1), and ephrin receptor A8 kinase (EPHA8). Together, these results support the utility of peptide array kinomic analyses in the generation of potential candidate kinases for future pancreatic cancer therapeutic development.
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Symons, Antony, Soren Beinke, and Steven C. Ley. "MAP kinase kinase kinases and innate immunity." Trends in Immunology 27, no. 1 (January 2006): 40–48. http://dx.doi.org/10.1016/j.it.2005.11.007.
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Wang, Pengcheng, Chuan-Chih Hsu, Yanyan Du, Peipei Zhu, Chunzhao Zhao, Xing Fu, Chunguang Zhang, et al. "Mapping proteome-wide targets of protein kinases in plant stress responses." Proceedings of the National Academy of Sciences 117, no. 6 (January 28, 2020): 3270–80. http://dx.doi.org/10.1073/pnas.1919901117.
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Protein kinases are major regulatory components in almost all cellular processes in eukaryotic cells. By adding phosphate groups, protein kinases regulate the activity, localization, protein–protein interactions, and other features of their target proteins. It is known that protein kinases are central components in plant responses to environmental stresses such as drought, high salinity, cold, and pathogen attack. However, only a few targets of these protein kinases have been identified. Moreover, how these protein kinases regulate downstream biological processes and mediate stress responses is still largely unknown. In this study, we introduce a strategy based on isotope-labeled in vitro phosphorylation reactions using in vivo phosphorylated peptides as substrate pools and apply this strategy to identify putative substrates of nine protein kinases that function in plant abiotic and biotic stress responses. As a result, we identified more than 5,000 putative target sites of osmotic stress-activated SnRK2.4 and SnRK2.6, abscisic acid-activated protein kinases SnRK2.6 and casein kinase 1-like 2 (CKL2), elicitor-activated protein kinase CDPK11 and MPK6, cold-activated protein kinase MPK6, H2O2-activated protein kinase OXI1 and MPK6, and salt-induced protein kinase SOS1 and MPK6, as well as the low-potassium-activated protein kinase CIPK23. These results provide comprehensive information on the role of these protein kinases in the control of cellular activities and could be a valuable resource for further studies on the mechanisms underlying plant responses to environmental stresses.
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Chowdhury, Iftekhar, Giovanna Dashi, and Salla Keskitalo. "CMGC Kinases in Health and Cancer." Cancers 15, no. 15 (July 28, 2023): 3838. http://dx.doi.org/10.3390/cancers15153838.
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CMGC kinases, encompassing cyclin-dependent kinases (CDKs), mitogen-activated protein kinases (MAPKs), glycogen synthase kinases (GSKs), and CDC-like kinases (CLKs), play pivotal roles in cellular signaling pathways, including cell cycle regulation, proliferation, differentiation, apoptosis, and gene expression regulation. The dysregulation and aberrant activation of these kinases have been implicated in cancer development and progression, making them attractive therapeutic targets. In recent years, kinase inhibitors targeting CMGC kinases, such as CDK4/6 inhibitors and BRAF/MEK inhibitors, have demonstrated clinical success in treating specific cancer types. However, challenges remain, including resistance to kinase inhibitors, off-target effects, and the need for better patient stratification. This review provides a comprehensive overview of the importance of CMGC kinases in cancer biology, their involvement in cellular signaling pathways, protein–protein interactions, and the current state of kinase inhibitors targeting these kinases. Furthermore, we discuss the challenges and future perspectives in targeting CMGC kinases for cancer therapy, including potential strategies to overcome resistance, the development of more selective inhibitors, and novel therapeutic approaches, such as targeting protein–protein interactions, exploiting synthetic lethality, and the evolution of omics in the study of the human kinome. As our understanding of the molecular mechanisms and protein–protein interactions involving CMGC kinases expands, so too will the opportunities for the development of more selective and effective therapeutic strategies for cancer treatment.
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TAYLOR, Ann T. S., Jitae KIM, and Philip S. LOW. "Involvement of mitogen-activated protein kinase activation in the signal-transduction pathways of the soya bean oxidative burst." Biochemical Journal 355, no. 3 (April 24, 2001): 795–803. http://dx.doi.org/10.1042/bj3550795.
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The oxidative burst constitutes one of the most rapid defence responses characterized in the Plant Kingdom. We have observed that four distinct elicitors of the soya bean oxidative burst activate kinases of masses ≈44kDa and ≈47kDa. Evidence that these kinases regulate production of reactive oxygen species include: (i) their rapid activation by oxidative burst elicitors, (ii) their tight temporal correlation between activation/deactivation of the kinases and activation/deactivation of the oxidative burst, (iii) the identical pharmacological profile of kinase activation and oxidant production for 13 commonly used inhibitors, and (iv) the autologous activation of both kinases and oxidant production by calyculin A and cantharidin, two phosphatase inhibitors. Immunological and biochemical studies reveal that the activated 44kDa and 47kDa kinases are mitogen-activated protein (MAP) kinase family members. The kinases prefer myelin basic protein as a substrate, and they phosphorylate primarily on threonine residues. The kinases are themselves phosphorylated on tyrosine residues, and this phosphorylation is required for activity. Finally, both kinases are recognized by an antibody against activated MAP kinase immediately after (but not before) cell stimulation by elicitors. Based on these and other observations, a preliminary sequence of signalling steps linking elicitor stimulation, kinase activation and Ca2+ entry, to initiation of oxidant production, is proposed.
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Kracht, M., O. Truong, N. F. Totty, M. Shiroo, and J. Saklatvala. "Interleukin 1 alpha activates two forms of p54 alpha mitogen-activated protein kinase in rabbit liver." Journal of Experimental Medicine 180, no. 6 (December 1, 1994): 2017–25. http://dx.doi.org/10.1084/jem.180.6.2017.
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We have identified in rabbits two hepatic forms of T669 peptide kinases that are very strongly activated after systemic injection with the inflammatory cytokine interleukin 1 (IL-1). The T669 peptide contains a major phosphorylation site of the epidermal growth factor receptor, threonine 699 and is a substrate for mitogen-activated protein (MAP) kinases. The kinases were purified to homogeneity and corresponded to 50- and 55-kD proteins on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Amino acid sequencing of 12 tryptic peptides of both kinases identified them as p54 MAP kinase alpha. This kinase belongs to the novel family of stress-activated protein kinases. This is the first evidence of IL-1 activating a specific protein kinase in vivo.
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Dong, Lily Q., and Feng Liu. "PDK2: the missing piece in the receptor tyrosine kinase signaling pathway puzzle." American Journal of Physiology-Endocrinology and Metabolism 289, no. 2 (August 2005): E187—E196. http://dx.doi.org/10.1152/ajpendo.00011.2005.
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Activation of members of the protein kinase AGC (cAMP dependent, cGMP dependent, and protein kinase C) family is regulated primarily by phosphorylation at two sites: a conserved threonine residue in the activation loop and a serine/threonine residue in a hydrophobic motif (HM) near the COOH terminus. Although phosphorylation of these kinases in the activation loop has been found to be mediated by phosphoinositide-dependent protein kinase-1 (PDK1), the kinase(s) that catalyzes AGC kinase phosphorylation in the HM remains uncharacterized. So far, at least 10 kinases have been suggested to function as an HM kinase or the so-called “PDK2,” including mitogen-activated protein (MAP) kinase-activated protein kinase-2 (MK2), integrin-linked kinase (ILK), p38 MAP kinase, protein kinase Cα (PKCα), PKCβ, the NIMA-related kinase-6 (NEK6), the mammalian target of rapamycin (mTOR), the double-stranded DNA-dependent protein kinase (DNK-PK), and the ataxia telangiectasia mutated (ATM) gene product. However, whether any or all of these kinases act as a physiological HM kinase remains to be established. Nonetheless, available data suggest that multiple systems may be used in cells to regulate the activation of the AGC family kinases. It is possible that, unlike activation loop phosphorylation, phosphorylation of the HM site in the different AGC family kinases is mediated by distinct kinases. In addition, phosphorylation of the AGC family kinase at the HM site could be cell type, signaling pathway, and substrate specific. Identification and characterization of the bonafide HM kinase(s) will be essential to verify these hypotheses.
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Jacinto, Estela, and Anja Lorberg. "TOR regulation of AGC kinases in yeast and mammals." Biochemical Journal 410, no. 1 (January 29, 2008): 19–37. http://dx.doi.org/10.1042/bj20071518.
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The TOR (target of rapamycin), an atypical protein kinase, is evolutionarily conserved from yeast to man. Pharmacological studies using rapamycin to inhibit TOR and yeast genetic studies have provided key insights on the function of TOR in growth regulation. One of the first bona fide cellular targets of TOR was the mammalian protein kinase p70 S6K (p70 S6 kinase), a member of a family of kinases called AGC (protein kinase A/protein kinase G/protein kinase C-family) kinases, which include PKA (cAMP-dependent protein kinase A), PKG (cGMP-dependent kinase) and PKC (protein kinase C). AGC kinases are also highly conserved and play a myriad of roles in cellular growth, proliferation and survival. The AGC kinases are regulated by a common scheme that involves phosphorylation of the kinase activation loop by PDK1 (phosphoinositide-dependent kinase 1), and phosphorylation at one or more sites at the C-terminal tail. The identification of two distinct TOR protein complexes, TORC1 (TOR complex 1) and TORC2, with different sensitivities to rapamycin, revealed that TOR, as part of either complex, can mediate phosphorylation at the C-terminal tail for optimal activation of a number of AGC kinases. Together, these studies elucidated that a fundamental function of TOR conserved throughout evolution may be to balance growth versus survival signals by regulating AGC kinases in response to nutrients and environmental conditions. This present review highlights this emerging function of TOR that is conserved from budding and fission yeast to mammals.
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Yamboliev, Ilia A., Jason C. Hedges, Jack L. M. Mutnick, Leonard P. Adam, and William T. Gerthoffer. "Evidence for modulation of smooth muscle force by the p38 MAP kinase/HSP27 pathway." American Journal of Physiology-Heart and Circulatory Physiology 278, no. 6 (June 1, 2000): H1899—H1907. http://dx.doi.org/10.1152/ajpheart.2000.278.6.h1899.
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Mitogen-activated protein (MAP) kinases signal to proteins that could modify smooth muscle contraction. Caldesmon is a substrate for extracellular signal-related kinases (ERK) and p38 MAP kinases in vitro and has been suggested to modulate actin-myosin interaction and contraction. Heat shock protein 27 (HSP27) is downstream of p38 MAP kinases presumably participating in the sustained phase of muscle contraction. We tested the role of caldesmon and HSP27 phosphorylation in the contractile response of vascular smooth muscle by using inhibitors of both MAP kinase pathways. In intact smooth muscle, PD-098059 abolished endothelin-1 (ET-1)-stimulated phosphorylation of ERK MAP kinases and caldesmon, but p38 MAP kinase activation and contractile response remained unaffected. SB-203580 reduced muscle contraction and inhibited p38 MAP kinase and HSP27 phosphorylation but had no effect on ERK MAP kinase and caldesmon phosphorylation. In permeabilized muscle fibers, SB-203580 and a polyclonal anti-HSP27 antibody attenuated ET-1-dependent contraction, whereas PD-098059 had no effect. These results suggest that ERK MAP kinases phosphorylate caldesmon in vivo but that activation of this pathway is unnecessary for force development. The generation of maximal force may be modulated by the p38 MAP kinase/HSP27 pathway.
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Bharucha, Nikë, Jun Ma, Craig J. Dobry, Sarah K. Lawson, Zhifen Yang, and Anuj Kumar. "Analysis of the Yeast Kinome Reveals a Network of Regulated Protein Localization during Filamentous Growth." Molecular Biology of the Cell 19, no. 7 (July 2008): 2708–17. http://dx.doi.org/10.1091/mbc.e07-11-1199.
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The subcellular distribution of kinases and other signaling proteins is regulated in response to cellular cues; however, the extent of this regulation has not been investigated for any gene set in any organism. Here, we present a systematic analysis of protein kinases in the budding yeast, screening for differential localization during filamentous growth. Filamentous growth is an important stress response involving mitogen-activated protein kinase and cAMP-dependent protein kinase signaling modules, wherein yeast cells form interconnected and elongated chains. Because standard strains of yeast are nonfilamentous, we constructed a unique set of 125 kinase-yellow fluorescent protein chimeras in the filamentous Σ1278b strain for this study. In total, we identified six cytoplasmic kinases (Bcy1p, Fus3p, Ksp1p, Kss1p, Sks1p, and Tpk2p) that localize predominantly to the nucleus during filamentous growth. These kinases form part of an interdependent, localization-based regulatory network: deletion of each individual kinase, or loss of kinase activity, disrupts the nuclear translocation of at least two other kinases. In particular, this study highlights a previously unknown function for the kinase Ksp1p, indicating the essentiality of its nuclear translocation during yeast filamentous growth. Thus, the localization of Ksp1p and the other kinases identified here is tightly controlled during filamentous growth, representing an overlooked regulatory component of this stress response.
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Amatya, Neha, David Yin-wei Lin, and Amy H. Andreotti. "Dynamic regulatory features of the protein tyrosine kinases." Biochemical Society Transactions 47, no. 4 (August 8, 2019): 1101–16. http://dx.doi.org/10.1042/bst20180590.
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Abstract The SRC, Abelson murine leukemia viral oncogene homolog 1, TEC and C-terminal SRC Kinase families of non-receptor tyrosine kinases (collectively the Src module kinases) mediate an array of cellular signaling processes and are therapeutic targets in many disease states. Crystal structures of Src modules kinases provide valuable insights into the regulatory mechanisms that control activation and generate a framework from which drug discovery can advance. The conformational ensembles visited by these multidomain kinases in solution are also key features of the regulatory machinery controlling catalytic activity. Measurement of dynamic motions within kinases substantially augments information derived from crystal structures. In this review, we focus on a body of work that has transformed our understanding of non-receptor tyrosine kinase regulation from a static view to one that incorporates how fluctuations in conformational ensembles and dynamic motions influence activation status. Regulatory dynamic networks are often shared across and between kinase families while specific dynamic behavior distinguishes unique regulatory mechanisms for select kinases. Moreover, intrinsically dynamic regions of kinases likely play important regulatory roles that have only been partially explored. Since there is clear precedence that kinase inhibitors can exploit specific dynamic features, continued efforts to define conformational ensembles and dynamic allostery will be key to combating drug resistance and devising alternate treatments for kinase-associated diseases.
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Frost, J. A., S. Xu, M. R. Hutchison, S. Marcus, and M. H. Cobb. "Actions of Rho family small G proteins and p21-activated protein kinases on mitogen-activated protein kinase family members." Molecular and Cellular Biology 16, no. 7 (July 1996): 3707–13. http://dx.doi.org/10.1128/mcb.16.7.3707.
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The mitogen-activated protein (MAP) kinases are a family of serine/threonine kinases that are regulated by distinct extracellular stimuli. The currently known members include extracellular signal-regulated protein kinase 1 (ERK1), ERK2, the c-Jun N-terminal kinase/stress-activated protein kinases (JNK/SAPKs), and p38 MAP kinases. We find that overexpression of the Ste20-related enzymes p21-activated kinase 1 (PAK1) and PAK2 in 293 cells is sufficient to activate JNK/SAPK and to a lesser extent p38 MAP kinase but not ERK2. Rat MAP/ERK kinase kinase 1 can stimulate the activity of each of these MAP kinases. Although neither activated Rac nor the PAKs stimulate ERK2 activity, overexpression of either dominant negative Rac2 or the N-terminal regulatory domain of PAK1 inhibits Ras-mediated activation of ERK2, suggesting a permissive role for Rac in the control of the ERK pathway. Furthermore, constitutively active Rac2, Cdc42hs, and RhoA synergize with an activated form of Raf to increase ERK2 activity. These findings reveal a previously unrecognized connection between Rho family small G proteins and the ERK pathway.
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SUZUKI, Tomohiko, Yasufumi YAMAMOTO, and Masahiro UMEKAWA. "Stichopus japonicus arginine kinase: gene structure and unique substrate recognition system." Biochemical Journal 351, no. 3 (October 24, 2000): 579–85. http://dx.doi.org/10.1042/bj3510579.
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Arginine kinase from the sea cucumber Stichopus japonicus underwent a unique molecular evolution. Unlike the monomeric 40kDa arginine kinases from molluscs and arthropods, Stichopus arginine kinase is dimeric, the same as cytoplasmic isoenzymes of the vertebrate creatine kinases. Its entire amino acid sequence is more similar to creatine kinases than to other arginine kinases, but the guanidino specificity region (GS region) is of the arginine kinase type. To elucidate its unusual evolution, the structure of the Stichopus arginine kinase gene was determined. It consisted of seven exons and six introns, and a part of the exon 2 of the Stichopus gene corresponds to the GS region. Compared with the structure of the human muscle creatine kinase gene (seven exons, six introns), the splice junctions of five introns were conserved exactly between the two genes, suggesting that these introns had been conserved for at least 500 million years. The entire sequence of Stichopus arginine kinase is distinctly included in the creatine kinase cluster in all tree construction methods examined. On the other hand, if the tree is constructed only from sequences corresponding to Stichopus exon 2, it is placed in the arginine kinase cluster. Thus we conclude that Stichopus arginine kinase evolved not from the arginine kinase gene but from the creatine kinase gene, and suggest that its GS region, determining substrate specificity, has been replaced by an arginine kinase type via exon shuffling. In typical arginine kinases four residues, Ser63, Gly64, Val65 and Tyr68 (numbering from the Limulus polyphemus sequence), in the GS region are highly conserved and are associated with substrate binding. Among them, Tyr68 appears to play a crucial role by forming a hydrogen bond with the substrate, and is conserved exactly in all arginine kinases. However, in Stichopus arginine kinase, none of these four conserved residues were present. Nevertheless, the enzyme displays an affinity for the substrate arginine (Km = 0.8mM) comparable with other arginine kinases. This implies that a completely different substrate-binding system has been developed in Stichopus arginine kinase. We propose that the His64 in Stichopus arginine kinase acts as a substitute for the Tyr68 in other arginine kinases, and that the imidazole ring of His64 is hydrogen bonded with the substrate arginine, thus stabilizing it.
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Póti, Ádám L., Laura Dénes, Kinga Papp, Csaba Bató, Zoltán Bánóczi, Attila Reményi, and Anita Alexa. "Phosphorylation-Assisted Luciferase Complementation Assay Designed to Monitor Kinase Activity and Kinase-Domain-Mediated Protein–Protein Binding." International Journal of Molecular Sciences 24, no. 19 (October 3, 2023): 14854. http://dx.doi.org/10.3390/ijms241914854.
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Protein kinases are key regulators of cell signaling and have been important therapeutic targets for three decades. ATP-competitive drugs directly inhibit the activity of kinases but these enzymes work as part of complex protein networks in which protein–protein interactions (often referred to as kinase docking) may govern a more complex activation pattern. Kinase docking is indispensable for many signaling disease-relevant Ser/Thr kinases and it is mediated by a dedicated surface groove on the kinase domain which is distinct from the substrate-binding pocket. Thus, interfering with kinase docking provides an alternative strategy to control kinases. We describe activity sensors developed for p90 ribosomal S6 kinase (RSK) and mitogen-activated protein kinases (MAPKs: ERK, p38, and JNK) whose substrate phosphorylation is known to depend on kinase-docking-groove-mediated protein–protein binding. The in vitro assays were based on fragment complementation of the NanoBit luciferase, which is facilitated upon substrate motif phosphorylation. The new phosphorylation-assisted luciferase complementation (PhALC) sensors are highly selective and the PhALC assay is a useful tool for the quantitative analysis of kinase activity or kinase docking, and even for high-throughput screening of academic compound collections.
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Zhang, Yangyang, Minghua Liu, Jun Wang, Jianlin Huang, Mingyue Guo, Ling Zuo, Biantiao Xu, Shousong Cao, and Xiukun Lin. "Targeting Protein Kinase Inhibitors with Traditional Chinese Medicine." Current Drug Targets 20, no. 15 (November 12, 2019): 1505–16. http://dx.doi.org/10.2174/1389450120666190802125959.
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Protein kinases play critical roles in the control of cell growth, proliferation, migration, and angiogenesis, through their catalytic activity. Over the past years, numerous protein kinase inhibitors have been identified and are being successfully used clinically. Traditional Chinese medicine (TCM) represents a large class of bioactive substances, and some of them display anticancer activity via inhibiting protein kinases signal pathway. Some of the TCM have been used to treat tumors clinically in China for many years. The p38mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase, serine/threonine-specific protein kinases (PI3K/AKT/mTOR), and extracellular signal-regulated kinases (ERK) pathways are considered important signals in cancer cell development. In the present article, the recent progress of TCM that exhibited significant inhibitory activity towards a range of protein kinases is discussed. The clinical efficacy of TCM with inhibitory effects on protein kinases in treating a tumor is also presented. The article also discussed the prospects and problems in the development of anticancer agents with TCM.
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Deznabi, Iman, Busra Arabaci, Mehmet Koyutürk, and Oznur Tastan. "DeepKinZero: zero-shot learning for predicting kinase–phosphosite associations involving understudied kinases." Bioinformatics 36, no. 12 (February 11, 2020): 3652–61. http://dx.doi.org/10.1093/bioinformatics/btaa013.
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Abstract Motivation Protein phosphorylation is a key regulator of protein function in signal transduction pathways. Kinases are the enzymes that catalyze the phosphorylation of other proteins in a target-specific manner. The dysregulation of phosphorylation is associated with many diseases including cancer. Although the advances in phosphoproteomics enable the identification of phosphosites at the proteome level, most of the phosphoproteome is still in the dark: more than 95% of the reported human phosphosites have no known kinases. Determining which kinase is responsible for phosphorylating a site remains an experimental challenge. Existing computational methods require several examples of known targets of a kinase to make accurate kinase-specific predictions, yet for a large body of kinases, only a few or no target sites are reported. Results We present DeepKinZero, the first zero-shot learning approach to predict the kinase acting on a phosphosite for kinases with no known phosphosite information. DeepKinZero transfers knowledge from kinases with many known target phosphosites to those kinases with no known sites through a zero-shot learning model. The kinase-specific positional amino acid preferences are learned using a bidirectional recurrent neural network. We show that DeepKinZero achieves significant improvement in accuracy for kinases with no known phosphosites in comparison to the baseline model and other methods available. By expanding our knowledge on understudied kinases, DeepKinZero can help to chart the phosphoproteome atlas. Availability and implementation The source codes are available at https://github.com/Tastanlab/DeepKinZero. Supplementary information Supplementary data are available at Bioinformatics online.
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Qi, Guangying, Jing Liu, Sisi Mi, Takaaki Tsunematsu, Shengjian Jin, Wenhua Shao, Tian Liu, Naozumi Ishimaru, Bo Tang, and Yasusei Kudo. "Aurora Kinase Inhibitors in Head and Neck Cancer." Current Topics in Medicinal Chemistry 18, no. 3 (May 14, 2018): 199–213. http://dx.doi.org/10.2174/1568026618666180112163741.
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Aurora kinases are a group of serine/threonine kinases responsible for the regulation of mitosis. In recent years, with the increase in Aurora kinase-related research, the important role of Aurora kinases in tumorigenesis has been gradually recognized. Aurora kinases have been regarded as a new target for cancer therapy, resulting in the development of Aurora kinase inhibitors. The study and application of these small-molecule inhibitors, especially in combination with chemotherapy drugs, represent a new direction in cancer treatment. This paper reviews studies on Aurora kinases from recent years, including studies of their biological function, their relationship with tumor progression, and their inhibitors.
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Khandekar, Sanjay S., Bingbing Feng, Tracey Yi, Susan Chen, Nicholas Laping, and Neal Bramson. "A Liquid Chromatography/Mass Spectrometry-Based Method for the Selection of ATP Competitive Kinase Inhibitors." Journal of Biomolecular Screening 10, no. 5 (August 2005): 447–55. http://dx.doi.org/10.1177/1087057105274846.
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The currently approved kinase inhibitors for therapeutic uses and a number of kinase inhibitors that are undergoing clinical trials are directed toward the adenosine triphosphate (ATP) binding site of protein kinases. The 5β-fluorosulfonylbenzoyl 5'-adenosine (FSBA) is an ATP-affinity reagent that covalently modifies a conserved lysine present in the nucleotide-binding site of most kinases. The authors have developed a liquid chromatography/mass spectrometry-basedmethod tomonitor binding ofATP competitive protein kinase inhibitors using FSBAas a nonselective activity-based probe for protein kinases. Their method provides a general, rapid, and reproducible means to screen and validate selective ATP competitive inhibitors of protein kinases.
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Ha, Geun-Hyoung, and Eun-Kyoung Yim Breuer. "Mitotic Kinases and p53 Signaling." Biochemistry Research International 2012 (2012): 1–14. http://dx.doi.org/10.1155/2012/195903.
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Mitosis is tightly regulated and any errors in this process often lead to aneuploidy, genomic instability, and tumorigenesis. Deregulation of mitotic kinases is significantly associated with improper cell division and aneuploidy. Because of their importance during mitosis and the relevance to cancer, mitotic kinase signaling has been extensively studied over the past few decades and, as a result, several mitotic kinase inhibitors have been developed. Despite promising preclinical results, targeting mitotic kinases for cancer therapy faces numerous challenges, including safety and patient selection issues. Therefore, there is an urgent need to better understand the molecular mechanisms underlying mitotic kinase signaling and its interactive network. Increasing evidence suggests that tumor suppressor p53 functions at the center of the mitotic kinase signaling network. In response to mitotic spindle damage, multiple mitotic kinases phosphorylate p53 to either activate or deactivate p53-mediated signaling. p53 can also regulate the expression and function of mitotic kinases, suggesting the existence of a network of mutual regulation, which can be positive or negative, between mitotic kinases and p53 signaling. Therefore, deciphering this regulatory network will provide knowledge to overcome current limitations of targeting mitotic kinases and further improve the results of targeted therapy.
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CHIARIELLO, Mario, Eliana GOMEZ, and J. Silvio GUTKIND. "Regulation of cyclin-dependent kinase (Cdk) 2 Thr-160 phosphorylation and activity by mitogen-activated protein kinase in late G1 phase." Biochemical Journal 349, no. 3 (July 25, 2000): 869–76. http://dx.doi.org/10.1042/bj3490869.
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Mitogen-activated protein (MAP) kinases, p42MAPK and p44MAPK, are central components of growth-promoting signalling pathways. However, how stimulation of MAP kinases culminates in cell-cycle progression is still poorly understood. Here we show that mitogenic stimulation of NIH 3T3 cells causes a sustained activation of MAP kinases, which lasts until cells begin progressing through the G1/S boundary. Furthermore, we observed that disruption of the MAP-kinase pathway with a selective MEK (MAP kinase/extracellular-signal-regulated protein kinase kinase) inhibitor, PD98059, prevents the activation of cyclin-dependent kinase (Cdk) 2 and DNA synthesis, even when added during late G1 phase, once the known mechanisms by which MAP kinase controls G1 progression, accumulation of G1 cyclins and degradation of Cdk inhibitors have already taken place. Moreover, we provide evidence indicating that MAP kinases control Cdk2 Thr-160 activating phosphorylation and function, possibly by regulating the activity of a Cdk-activating kinase, thus promoting the re-initiation of DNA synthesis. These findings suggest the existence of a novel mechanism whereby signal-transducing pathways converging on MAP kinases can affect the cell-cycle machinery and, ultimately, participate in cell-growth control.
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Wen, X., H. H. Lin, and D. K. Ann. "Salivary Cellular Signaling and Gene Regulation." Advances in Dental Research 14, no. 1 (December 2000): 76–80. http://dx.doi.org/10.1177/08959374000140011201.
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Protein tyrosine kinase and protein serine kinase activation has been implicated in the regulation of salivary cell proliferation and differentiation. Aberrant expression and alterations of certain tyrosine or serine kinases, such as Raf or erbB2, are known to trigger salivary tumor development (Li et al., 1997; Cho et al., 1999). It has been estimated that there are about 1000 to 2000 protein kinases in the mammalian genome, with 100 to 200 of them ( i.e., 10%) being tyrosine kinase (Hanks and Hunter, 1995). At present, there are approximately 85 different tyrosine kinases identified in the GenBank database. Based on the relatively slow rate of discovery in the past few years, 100 is a better approximation of the total number of tyrosine kinases encoded by each mammalian genome. It is reasonable to assume that there are about 30 to 50 tyrosine kinases expressed in a given cell at a given differentiation/proliferation stage. This number is large enough to provide a characteristic tissue-specific tyrosine kinase expression profile, but small enough to be identified in a simple screening. The hope for tyrosine kinases as differentiation or proliferation markers rests with the possibility for the identification and characterization of a differentiation/proliferation stage-specific expression pattern in salivary cells. Several ligands that transmit signal through receptor tyrosine kinases and/or Ras/Raf/ERK kinases have been extensively studied in salivary cells. This review focuses mainly on the signaling pathways activated bv Raf and Etk.
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Yamboliev, Ilia A., Jennifer Chen, and William T. Gerthoffer. "PI 3-kinases and Src kinases regulate spreading and migration of cultured VSMCs." American Journal of Physiology-Cell Physiology 281, no. 2 (August 1, 2001): C709—C718. http://dx.doi.org/10.1152/ajpcell.2001.281.2.c709.
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Pulmonary artery smooth muscle cell (PASMC) adhesion, spreading, and migration depend on matrix-stimulated reorganization of focal adhesions. Platelet-derived growth factor (PDGF) activates intracellular signal transduction cascades that also regulate adhesion, spreading, and migration, but the signaling molecules involved in these events are poorly defined. We hypothesized that phosphatidylinositol (PI) 3-kinases and Src tyrosine kinases translate matrix and PDGF-initiated signals into cell motility. In experiments with cultured canine PASMCs, inhibition of PI 3-kinases with wortmannin (0.3 μM) and LY-294002 (50 μM) and of Src kinase with PP1 (30 μM) did not decrease spontaneous (nonstimulated) or PDGF-stimulated (10 ng/ml) adhesion onto collagen. PI 3-kinase and Src kinase activities, however, were necessary for cell spreading: PP1 inhibited cell spreading and Src Tyr-418 phosphorylation in a concentration-dependent manner. Inhibition of PI 3-kinase and Src partially reduced cell migration, while at 10 and 30 μM, PP1 eliminated migration, likely due to inhibition of PDGF receptors. In conclusion, both PI 3-kinases and Src tyrosine kinases are components of pathways that mediate spreading and migration of cultured PASMCs on collagen.
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Ravi, Srimadhavi, Bhanu Priya, Pankaj Dubey, Vijay Thiruvenkatam, and Sivapriya Kirubakaran. "Molecular Docking and Molecular Dynamics Simulation Studies of Quinoline-3-Carboxamide Derivatives with DDR Kinases–Selectivity Studies towards ATM Kinase." Chemistry 3, no. 2 (April 11, 2021): 511–24. http://dx.doi.org/10.3390/chemistry3020036.
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Quinoline-3-carboxamides are an essential class of drug-like small molecules that are known to inhibit the phosphatidylinositol 3-kinase-related kinases (PIKK) family kinases. The quinoline nitrogen is shown to bind to the hinge region of the kinases, making them competitive inhibitors of adenosine triphosphate (ATP). We have previously designed and synthesized quinoline-3-carboxamides as potential ataxia telangiectasia mutated (ATM) kinase inhibitors to function as an adjuvant treatment with DNA damaging agents. This article discusses the molecular docking studies performed with these derivatives with the DNA damage and response (DDR) kinases-ATM, ataxia telangiectasia and rad3 related (ATR), and DNA dependent protein kinase catalytic subunit (DNA-PKcs) and highlights their selectivity towards ATM kinase. Docking studies were also performed with mTOR and PI3Kγ, which are close homologs of the DDR kinases. Molecular dynamics simulations were performed for one of the inhibitors against all the enzymes to establish the stability of the interactions involved. Finally, the absorption, distribution, metabolism, and excretion (ADME) properties of the inhibitors were predicted using the QikProp manual in Maestro. In conclusion, the molecules synthesized showed high selectivity towards the ATM kinase in comparison with the other kinases, though the sequence similarity between them was relatively high.
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Anderson, Brian, Peter Rosston, Han Wee Ong, Mohammad Anwar Hossain, Zachary W. Davis-Gilbert, and David H. Drewry. "How many kinases are druggable? A review of our current understanding." Biochemical Journal 480, no. 16 (August 29, 2023): 1331–63. http://dx.doi.org/10.1042/bcj20220217.
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There are over 500 human kinases ranging from very well-studied to almost completely ignored. Kinases are tractable and implicated in many diseases, making them ideal targets for medicinal chemistry campaigns, but is it possible to discover a drug for each individual kinase? For every human kinase, we gathered data on their citation count, availability of chemical probes, approved and investigational drugs, PDB structures, and biochemical and cellular assays. Analysis of these factors highlights which kinase groups have a wealth of information available, and which groups still have room for progress. The data suggest a disproportionate focus on the more well characterized kinases while much of the kinome remains comparatively understudied. It is noteworthy that tool compounds for understudied kinases have already been developed, and there is still untapped potential for further development in this chemical space. Finally, this review discusses many of the different strategies employed to generate selectivity between kinases. Given the large volume of information available and the progress made over the past 20 years when it comes to drugging kinases, we believe it is possible to develop a tool compound for every human kinase. We hope this review will prove to be both a useful resource as well as inspire the discovery of a tool for every kinase.
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Shin, Soon, Youngshim Lee, Beom Kim, Junho Lee, Seunghyun Ahn, Dongsoo Koh, Yoongho Lim, and Young Lee. "Inhibitory Effect of Synthetic Flavone Derivatives on Pan-Aurora Kinases: Induction of G2/M Cell-Cycle Arrest and Apoptosis in HCT116 Human Colon Cancer Cells." International Journal of Molecular Sciences 19, no. 12 (December 17, 2018): 4086. http://dx.doi.org/10.3390/ijms19124086.
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Members of the aurora kinase family are Ser/Thr kinases involved in regulating mitosis. Multiple promising clinical trials to target aurora kinases are in development. To discover flavones showing growth inhibitory effects on cancer cells, 36 flavone derivatives were prepared, and their cytotoxicity was measured using a long-term clonogenic survival assay. Their half-maximal growth inhibitory effects against HCT116 human colon cancer cells were observed at the sub-micromolar level. Pharmacophores were derived based on three-dimensional quantitative structure–activity calculations. Because plant-derived flavones inhibit aurora kinase B, we selected 5-methoxy-2-(2-methoxynaphthalen-1-yl)-4H-chromen-4-one (derivative 31), which showed the best half-maximal cell growth inhibitory effect, and tested whether it can inhibit aurora kinases in HCT116 colon cancer cells. We found that derivative 31 inhibited the phosphorylation of aurora kinases A, aurora kinases B and aurora kinases C, suggesting that derivative 31 is a potential pan-aurora kinase inhibitor. The results of our analysis of the binding modes between derivative 31 and aurora A and aurora B kinases using in-silico docking were consistent with the pharmacophores proposed in this study.
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Foukas, L. C., and P. R. Shepherd. "Phosphoinositide 3-kinase: the protein kinase that time forgot." Biochemical Society Transactions 32, no. 2 (April 1, 2004): 330–31. http://dx.doi.org/10.1042/bst0320330.
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Class I phosphoinositide 3-kinases were originally characterized as lipid kinases, although more than 10 years ago they were also found to phosphorylate protein serine residues. However, while there is a vast amount of data on the function of this lipid kinase activity, relatively little is known about the function of the protein kinase activity. We discuss the evidence that suggests that the protein kinase activity of phosphoinositide 3-kinases mediates important signalling functions in cells.
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Lenormand, P., C. Sardet, G. Pagès, G. L'Allemain, A. Brunet, and J. Pouysségur. "Growth factors induce nuclear translocation of MAP kinases (p42mapk and p44mapk) but not of their activator MAP kinase kinase (p45mapkk) in fibroblasts." Journal of Cell Biology 122, no. 5 (September 1, 1993): 1079–88. http://dx.doi.org/10.1083/jcb.122.5.1079.
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Mitogen-activated protein kinases (p42mapk and p44mapk) are serine/threonine kinases that are activated rapidly in cells stimulated with various extracellular signals. This activation is mediated via MAP kinase kinase (p45mapkk), a dual specificity kinase which phosphorylates two key regulatory threonine and tyrosine residues of MAP kinases. We reported previously that the persistent phase of MAP kinase activation is essential for mitogenically stimulated cells to pass the "restriction point" of the cell cycle. Here, using specific polyclonal antibodies and transfection of epitope-tagged recombinant MAP kinases we demonstrate that these signaling protein kinases undergo distinct spatio-temporal localization in growth factor-stimulated cells. In G0-arrested hamster fibroblasts the activator p45mapkk and MAP kinases (p42mapk, p44mapk) are mainly cytoplasmic. Subsequent to mitogenic stimulation by serum or alpha-thrombin both MAP kinase isoforms translocate into the nucleus. This translocation is rapid (seen in 15 min), persistent (at least during the entire G1 period up to 6 h), reversible (by removal of the mitogenic stimulus) and apparently 'coupled' to the mitogenic potential; it does not occur in response to nonmitogenic agents such as alpha-thrombin-receptor synthetic peptides and phorbol esters that fail to activate MAP kinases persistently. When p42mapk and p44mapk are expressed stably at high levels, they are found in the nucleus of resting cells; this nuclear localization is also apparent with kinase-deficient mutants (p44mapk T192A or Y194F). In marked contrast the p45mapkk activator remains cytoplasmic even during prolonged growth factor stimulation and even after high expression levels achieved by transfection. We propose that the rapid and persistent nuclear transfer of p42mapk and p44mapk during the entire G0-G1 period is crucial for the function of these kinases in mediating the growth response.
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Takekawa, Mutsuhiro, Kazuo Tatebayashi, and Haruo Saito. "Conserved Docking Site Is Essential for Activation of Mammalian MAP Kinase Kinases by Specific MAP Kinase Kinase Kinases." Molecular Cell 18, no. 3 (April 2005): 295–306. http://dx.doi.org/10.1016/j.molcel.2005.04.001.
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Zhang, Huairong, Bo Gao, and Bingyin Shi. "Identification of Differentially Expressed Kinase and Screening Potential Anticancer Drugs in Papillary Thyroid Carcinoma." Disease Markers 2016 (2016): 1–9. http://dx.doi.org/10.1155/2016/2832980.
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Aim. We aim to identify protein kinases involved in the pathophysiology of papillary thyroid carcinoma (PTC) in order to provide potential therapeutic targets for kinase inhibitors and unfold possible molecular mechanisms.Materials and Methods. The gene expression profile of GSE27155 was analyzed to identify differentially expressed genes and mapped onto human protein kinases database. Correlation of kinases with PTC was addressed by systematic literature search, GO and KEGG pathway analysis.Results. The functional enrichment analysis indicated that “mitogen-activated protein kinases pathway” expression was extremely enriched, followed by “neurotrophin signaling pathway,” “focal adhesion,” and “GnRH signaling pathway.” MAPK, SRC, PDGFRa, ErbB, and EGFR were significantly regulated to correct these pathways. Kinases investigated by the literature on carcinoma were considered to be potential novel molecular therapeutic target in PTC and application of corresponding kinase inhibitors could be possible therapeutic tool.Conclusion. SRC, MAPK, and EGFR were the most important differentially expressed kinases in PTC. Combined inhibitors may have high efficacy in PTC treatment by targeting these kinases.
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Gerthoffer, W. T., I. A. Yamboliev, J. Pohl, R. Haynes, S. Dang, and J. McHugh. "Activation of MAP kinases in airway smooth muscle." American Journal of Physiology-Lung Cellular and Molecular Physiology 272, no. 2 (February 1, 1997): L244—L252. http://dx.doi.org/10.1152/ajplung.1997.272.2.l244.
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To test the hypothesis that mitogen-activated protein (MAP) kinases are activated by contractile agonists in intact nonproliferating airway smooth muscle, kinase activities were compared in resting and stimulated canine tracheal smooth muscle. Kinase activities in sodium dodecyl sulfate extracts were assayed by a gel renaturation method. Myelin basic protein kinase activities corresponding to ERK1 and ERK2 immunoreactive proteins were activated twofold above the basal level within 5 min by 1 microM carbachol. MAP kinase activity assayed in crude homogenates using a synthetic peptide substrate (APRTPGGRR) also increased twofold above basal in muscles stimulated with 1 microM carbachol. Two protein kinases separated by Mono-Q chromatography were identified on Western blots as ERK1 and ERK2 MAP kinases. Carbachol stimulation increased caldesmon phosphorylation in intact muscle, and purified caldesmon was a substrate for activated murine ERK2 MAP kinase. Activated ERK2 MAP kinase added to Triton X-100-permeabilized fibers potentiated Ca2+-induced contraction. The results show that ERK MAP kinases are activated after stimulation of muscarinic receptors in airway smooth muscle, which is consistent with coupling of MAP kinases to phosphorylation of caldesmon in vivo.
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Cook, Amy K., Michael Carty, Cherie A. Singer, Ilia A. Yamboliev, and William T. Gerthoffer. "Coupling of M2 muscarinic receptors to ERK MAP kinases and caldesmon phosphorylation in colonic smooth muscle." American Journal of Physiology-Gastrointestinal and Liver Physiology 278, no. 3 (March 1, 2000): G429—G437. http://dx.doi.org/10.1152/ajpgi.2000.278.3.g429.
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Coupling of M2 and M3 muscarinic receptors to activation of mitogen-activated protein (MAP) kinases and phosphorylation of caldesmon was studied in canine colonic smooth muscle strips in which M3 receptors were selectively inactivated by N, N-dimethyl-4-piperidinyl diphenylacetate (4-DAMP) mustard (40 nM). ACh elicited activation of extracellular signal-regulated kinase (ERK) 1, ERK2, and p38 MAP kinases in control muscles and increased phosphorylation of caldesmon (Ser789), a putative downstream target of MAP kinases. Alkylation of M3 receptors with 4-DAMP had only a modest inhibitory effect on ERK activation, p38 MAP kinase activation, and caldesmon phosphorylation. Subsequent treatment with 1 μM AF-DX 116 completely prevented activation of ERK and p38 MAP kinase and prevented caldesmon phosphorylation. Caldesmon phosphorylation was blocked by the MAP kinase/ERK kinase inhibitor PD-98509 but not by the p38 MAP kinase inhibitor SB-203580. These results indicate that colonic smooth muscle M2 receptors are coupled to ERK and p38 MAP kinases. Activation of ERK, but not p38 MAP kinases, results in phosphorylation of caldesmon in vivo, which is a novel function for M2receptor activation in smooth muscle.
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Purcell, Angela L., and Thomas J. Carew. "Modulation of Excitability in Aplysia Tail Sensory Neurons by Tyrosine Kinases." Journal of Neurophysiology 85, no. 6 (June 1, 2001): 2398–411. http://dx.doi.org/10.1152/jn.2001.85.6.2398.
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Tyrosine kinases have recently been shown to modulate synaptic plasticity and ion channel function. We show here that tyrosine kinases can also modulate both the baseline excitability state of Aplysia tail sensory neurons (SNs) as well as the excitability induced by the neuromodulator serotonin (5HT). First, we examined the effects of increasing and decreasing tyrosine kinase activity in the SNs. We found that tyrosine kinase inhibitors decrease baseline SN excitability in addition to attenuating the increase in excitability induced by 5HT. Conversely, functionally increasing cellular tyrosine kinase activity in the SNs by either inhibiting opposing tyrosine phosphatase activity or by direct injection of an active tyrosine kinase (Src) induces increases in SN excitability in the absence of 5HT. Second, we examined the interaction between protein kinase A (PKA), which is known to mediate 5HT-induced excitability changes in the SNs, and tyrosine kinases, in the enhancement of SN excitability. We found that the tyrosine kinases function downstream of PKA activation since tyrosine kinase inhibitors reduce excitability induced by activators of PKA. Finally, we examined the role of tyrosine kinases in other forms of 5HT-induced plasticity in the SNs. We found that while tyrosine kinase inhibitors attenuate excitability produced by 5HT, they have no effect on short-term facilitation (STF) of the SN-motor neuron (MN) synapse induced by 5HT. Thus tyrosine kinases modulate different forms of SN plasticity independently. Such differential modulation would have important consequences for activity-dependent plasticity in a variety of neural circuits.
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Eto, Masumi, Shuichi Katsuki, Yoshinori Tanaka, and Kosuke Takeya. "Kinase activity-tagged western blotting assay." BioTechniques 68, no. 4 (April 2020): 211–13. http://dx.doi.org/10.2144/btn-2019-0136.
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Determining cellular activities of protein kinases is a fundamental step for characterizing pathophysiological cell signaling pathways. Here, we optimized a nonradioactive method that detects protein kinases in tissues or cells after separation by SDS-PAGE and transfer onto polyvinylidene fluoride membranes. The method, kinase activity-tagged western blotting (KAT-WB), consists of five steps: electrophoresis of cell extracts that contain protein kinases, electroblotting proteins onto polyvinylidene fluoride membrane, denaturation–renaturation, phosphorylation, with or without an added substrate protein and immunodetection using anti-phospho-specific antibodies. KAT-WB detected autophosphorylation of one Tyr-kinase and site-specific phosphorylation of added substrate by multiple kinases. KAT-WB assay enables us to interrogate multiple kinase signaling pathways without using radioactive ATP.
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Rane, M. J., S. L. Carrithers, J. M. Arthur, J. B. Klein, and K. R. McLeish. "Formyl peptide receptors are coupled to multiple mitogen-activated protein kinase cascades by distinct signal transduction pathways: role in activation of reduced nicotinamide adenine dinucleotide oxidase." Journal of Immunology 159, no. 10 (November 15, 1997): 5070–78. http://dx.doi.org/10.4049/jimmunol.159.10.5070.
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Abstract Formyl peptide receptor activation of three mitogen-activated protein kinase (MAPK) cascades, extracellular signal-regulated kinases (ERKs), N-terminal kinases (JNKs), and p38 MAPK was examined in differentiated HL-60 granulocytes. FMLP stimulated a concentration- and time-dependent increase in ERK, JNK, and p38 MAPK activities, all of which were dependent on a pertussis toxin-sensitive G protein. Pharmacologic inhibitors were used to examine the roles of tyrosine kinases, phosphatidylinositol 3-kinase, protein kinase C, and phospholipase C. FMLP-stimulated ERK activity was dependent on tyrosine kinases, phosphatidylinositol 3-kinase, protein kinase C, and phospholipase C; p38 MAPK activation was dependent on phosphatidylinositol 3-kinase and phospholipase C; while JNK activation was independent of all of these signaling components. The mitogen-activated protein kinase/ERK kinase inhibitor PD098059 reduced ERK activation by 90%, while an inhibitor of p38 MAPK, SB203580, inhibited p38 MAPK activation by 80%. Both PD098059 and SB203580 inhibited FMLP-stimulated superoxide release, as did inhibitors directed against protein kinase C, tyrosine kinases, and phosphatidylinositol 3-kinase. We conclude that formyl peptide receptors are coupled to three MAPK cascades by Gi proteins. ERKs, p38 MAPK, and JNKs are each activated by distinct proximal signal transduction pathways. Activation of p38 MAPK is necessary for FMLP stimulation of respiratory burst activity; however, a second signal that may involve ERK is also required for this activity.
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Attwood, Paul V. "Histidine kinases from bacteria to humans." Biochemical Society Transactions 41, no. 4 (July 18, 2013): 1023–28. http://dx.doi.org/10.1042/bst20130019.
Full textAbstract:
It is more than 50 years since protein histidine phosphorylation was first discovered in 1962 by Boyer and co-workers; however, histidine kinases are still much less well recognized than the serine/threonine and tyrosine kinases. The best-known histidine kinases are the two-component signalling kinases that occur in bacteria, fungi and plants. The mechanisms and functions of these kinases, their cognate response regulators and associated phosphorelay proteins are becoming increasingly well understood. When genomes of higher eukaryotes began to be sequenced, it did not appear that they contained two-component histidine kinase system homologues, apart from a couple of related mitochondrial enzymes that were later shown not to function as histidine kinases. However, as a result of the burgeoning sequencing of genomes from a wide variety of eukaryotic organisms, it is clear that there are proteins that correspond to components of the two-component histidine kinase systems in higher eukaryotes and that operational two-component kinase systems are likely to occur in these organisms. There is unequivocal direct evidence that protein histidine phosphorylation does occur in mammals. So far, only nucleoside diphosphate kinases have been shown to be involved in protein histidine phosphorylation, but their mechanisms of action are not well understood. It is clear that other, yet to be identified, histidine kinases also exist in mammals and that protein histidine phosphorylation may play important roles in higher eukaryotes.