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Tables
Protein Kinase Tables Home
Overview
Protein tyrosine kinases (PTKs) are enzymes which catalyze the phosphorylation of tyrosine residues. Now that the
genome project has been completed, it seems that the total number of PTKs does not exceed 1000. There are two main classes
of PTKs: receptor PTKs and cellular, or non-receptor, PTKs. Of the 91 protein tyrosine kinases identified thus far, 59
are receptor tyrosine kinases and 32 are non-receptor tyrosine kinases. These enzymes are involved in cellular signaling
pathways and regulate key cell functions such as proliferation, differentiation, anti-apoptotic signaling and neurite
outgrowth. Unregulated activation of these enzymes, through mechanisms such as point mutations or over-expression, can
lead to various forms of cancer as well as benign proliferative conditions. Indeed, more than 70% of the known oncogenes
and proto-oncogenes involved in cancer code for PTKs. The importance of PTKs in health and disease is further underscored
by the existence of aberrations in PTK signaling occurring in inflammatory diseases and diabetes.
Receptor PTKs possess an extracellular ligand binding domain, a transmembrane domain and an intracellular catalytic
domain. The transmembrane domain anchors the receptor in the plasma membrane, while the extracellular domains bind growth
factors. Characteristically, the extracellular domains are comprised of one or more identifiable structural motifs,
including cysteine-rich regions, fibronectin III-like domains, immunoglobulin-like domains, EGF-like domains, cadherin-like
domains, kringle-like domains, Factor VIII-like domains, glycine-rich regions, leucine-rich regions, acidic regions and
discoidin-like domains.
The intracellular kinase domains of receptor PTKs can be divided into two classes: those containing a stretch of amino
acids separating the kinase domain and those in which the kinase domain is continuous. Activation of the kinase is achieved
by ligand binding to the extracellular domain, which induces dimerization of the receptors. Receptors thus activated are
able to autophosphorylate tyrosine residues outside the catalytic domain via cross-phosphorylation. The results of this
auto-phosphorylation are stabilization of the active receptor conformation and the creation of phosphotyrosine docking
sites for proteins which transduce signals within the cell. Signaling proteins which bind to the intracellular domain of
receptor tyrosine kinases in a phosphotyrosine-dependent manner include RasGAP, PI3-kinase, phospholipase C
 , phosphotyrosine phosphatase SHP and
adaptor proteins such as Shc, Grb2 and Crk.
In contrast to receptor PTKs, cellular PTKs are located in the cytoplasm, nucleus or anchored to the inner leaflet of
the plasma membrane. They are grouped into eight families: SRC, JAK, ABL, FAK, FPS, CSK, SYK and BTK. Each family consists
of several members. With the exception of homologous kinase domains (Src Homology 1, or SH1 domains), and some protein-
protein interaction domains (SH2 and SH3 domains), they have little in common, structurally. Of those cellular PTKs whose
functions are known, many, such as SRC, are involved in cell growth. In contrast, FPS PTKs are involved in differentiation,
ABL PTKs are involved in growth inhibition, and FAK activity is associated with cell adhesion. Some members of the cytokine
receptor pathway interact with JAKs, which phosphorylate the transcription factors, STATs. Still other PTKs activate
pathways whose components and functions remain to be determined.
Key References:
Anafi, M., et al. Tyrphostin-induced inhibition of p210bcr-abl tyrosine kinase activity induces K562 to differentiate."
Blood, 82, 3524-3529 (1993).
Blum, G., et al. "Substrate competitive inhibitors of the IGF-1 receptor kinase." Biochemistry, 39,
15705- 15712 (2000).
Buchdunger, E., et al. "4,5-Dianilinophthalimide: A protein tyrosine kinase inhibitor with selectivity for the epidermal
growth factor receptor signal transduction pathway and potent in vivo antitumor activity." Proc. Natl. Acad. Sci.
USA, 91, 2334-2338 (1994).
Fry, D.W., et al. "A specific inhibitor of the epidermal growth factor receptor tyrosine kinase." Science, 265
, 1093-1095 (1994).
Hanke, J.H., et al. "Discovery of a novel, potent, and Src family-selective tyrosine kinase inhibitor." J. Biol. Chem., 271, 695-701 (1996).
Kovalenko, M., et al. "Selective platelet derived growth factor receptor kinase blockers reverse sis-transformation." Cancer Res., 54, 6106-6114, (1994).
Levitzki, A., "Protein tyrosine kinase inhibitors as therapeutic agents." Pharmacol. Ther., 82, 231-239 (1999).
Levitzki, A. and Gazit, A. "Tyrosine kinase inhibition: An approach to drug development." Science, 257, 1782-1788 (1995).
Mohammadi, B.K., et al. "Structures of the tyrosine kinase domain of fibroblast growth factor receptor complex with inhibitors." Science, 276, 955-960 (1997).
Osherov, N. and Levitzki, A. "Epidermal growth factor dependent activation of Src family kinases." Eur. J. Biochem., 225, 1047-1053 (1994).
Osherov, N., et al. "Selective inhibition of the FGF and HER2/Neu receptors by tyrphostins." J. Biol. Chem., 268, 11134-11142 (1993).
Parrizas, M., et al. "Specific inhibition of insulin-like growth factor-1 and insulin receptor tyrosine kinase activity and biological function by tyrphostins." Endocrinology, 138, 1427-1433 (1997).
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