Src family kinases

Dasatinib (Spry cel) TKI Bcr-Abl, Src family kinases, c-Kit, PDGFR, EphB4 Inhibition of kinase activity - ATP-competitive, binding to an active conformation CML ALL... 

Though a large number of small molecule inhibitors against a variety of tyrosine kinases are being developed, the most advanced drugs can be roughly classified as (i) Bcr-Abl/Src family kinase inhibitors, (ii) ErbB inhibitors and (iii) broad spectrum TfCIs with an anti-angiogenic component. 

Thomas SM, Brugge JS (1997) Cellular functions regulated by Src family kinases. Annu Rev Cell Dev Biol 13 513-609... 

Like all immunoreceptor family members, FceRI lacks intrinsic tyrosine kinase activity. IgE and antigen-induced crosshnking of FceRI initiates a complex series of phosphate transfer events via the activation of non-receptor Src, Syk and Tec family protein tyrosine kinases (fig. 1). The Src family kinase Lyn, which associates with the FceRI p subunit in mast cells, transphosphorylates neighboring FceRI ITAMs after receptor aggregation [7, 26]. Once phosphorylated, the p chain ITAM binds to the SH2 domain of additional Lyn molecules, while the phosphorylated y chain ITAM recruits Syk to the receptor complex, where it is activated by both autophosphorylation and phosphorylation by Lyn [2, 7,15, 26]. 

In addition to Lyn, a second Src family kinase, Fyn, associates with the FceRI P chain and is activated after FceRI aggregation [26]. Fyn phosphorylates the adaptor Gab2 to activate the phosphatidyUnositol-3-OH kinase (PI3K) pathway the SH2 domain-... 

Hong H, Kitaura J, Xiao W, Horejsi V, Ra C, Lowell CA, Kawakami Y Kawakami X Xhe Src family kinase Hck regulates mast cell activation by suppressing an inhibitory Src family kinase Lyn. Blood 2007 110 2511-2519. 

Several chemokines have been shown to stimulate tyrosine phosphorylation with evidence for activation of both Src family kinases (40) as well as Jak2/3 (41). However, recent lines of evidence provide compelling evidence that... 

The key in activation of Src family kinases is the disruption of intramolecular interactions and relief of autoinhibition. In addition to dephosphorylation of Y527 by PTPs, the SH2-phosphoY527 bond can be disrupted by competition with a high affinity phosphotyrosine ligand. 

Zhou, H. R., Jia Q., and Pestka J.J. Ribotoxic stress response to the trichothecene deoxyni-valenol in the macrophage involves the SRC family kinase Hck. Toxicol. Sci. 85,916,2005. 

Ernst, M. et al. Constitutive activation of the SRC family kinase Hck results in spontaneous pulmonary inflammation and an enhanced innate immune response. J. Exp. Med. 196, 589, 2002. 

Chen P, Doweyko AM, Norris D, et al. Imidazo-quinoxahne Src-family kinase p56 inhibitors SAR, QSAR, and the discovery of (S)-N-(2-chloro-6-methylphenyl)-2-(3-methyl-l-piper-azinyl) imidazo [l,5-a]pyrido[3,2-e]pyrazin-6-amine (BMS-279700) as a potent and orally active inhibitor with excellent in vivo antiinflammatory activity J Med Chem 2004 47, 4517-29. 

Keywords Src Src family kinases Kinase selectivity Structure-based design Mechanism-based design... 

Src is the prototype of the superfamily of protein tyrosine kinases and was one of the first protein kinases to be characterized by various genetic, cellular, and structure-function studies to help imderstand its role in signal transduction pathways as well as in disease processes, including cancer, osteoporosis, and both tumor- and inflammation-mediated bone loss [28-38]. In fact, studies on Src provided some of the first evidence correlating protein kinase activity and substrate protein phosphorylation in the regulation of signal transduction pathways relative to normal cellular activity as well as mahgnant transformations. Src family kinases include Fyn, Yes, Yrk, Blk, Fgr, Hck, Lyn,... 

Fig. 3. A simplified illustration of BCR-ABL and SRC family kinase involvement in oncogenic signaling pathways. The inhibitory effect is indicated by the upside-down T s. ABL = Abelson tyrosine kinase BCR = breakpoint cluster region FAK = focal adhesion kinase Grb-2 = growth factor receptor-bound protein 2 HcK = hematopoietic cell kinase JNK = Jun amino-terminal kinase P = phosphate group PI3 K = phosphatidylinositol-3-kinase SFK = SRC family kinases StatS = signal transducer and activator of transcription 5. (Reprinted with permission from Ref (123)). 

If one takes CML cells and cultures them in the presence of IM, or obtains cells from patients who have progressed while on IM therapy, a decrease in BCR-ABL1 mRNA or protein levels is seen with a concomitant increase in SRC family kinases (44). If one inhibits LYN expression by RNA interference in IM-resistant CML cells, survival and proliferation of these cells is inhibited (48). Additional support for the role of SRC kinases in some patients with IM resistance is that IM is unable to directly inhibit SRC kinases but does so only through its effect on BCR-ABLl (49). 

Wilson MB, Schreiner SJ, Choi HJ et al. Selective pyrrolo-pyrimidine inhibitors reveal a necessary role for SRC family kinases in BCR-ABL signal transduction and oncogenesis. Oncogene 2002 21 8075-8088. 

Donato N, Wu J, Kong LY et al. Constitutive activation of SRC-family kinases in chronic myelogenous leukemia patients resistant to imatinib mesylate in the absence of BCR-ABL mutations a rationale use of SRC/ABL dual kinase inhibitor-based therapy (Abstract 1087). B/oo<7 2005 106 316a. 

Hofmeister JK, Cooney D, Coggeshall KM. Clustered CD20 induced apoptosis src-family kinase, the proximal regulator of tyrosine phosphorylation, calcium influx, and caspase 3-dependent apoptosis. Blood Cells Mol Dis 2000 26 133-143. 

Despite this complexity, most integrins share two, key interrelated functions first, to promote the assembly and organization of the actin cytoskeleton [122, 123] and second, to regulate signal transduction cascades [124-126], Spanning the cell membrane, these subunits serve as a communication pathway, linking the actin cytoskeleton and intracellular cytoplasmic proteins involved in focal adhesion complexes (FACs) with the cell s dynamic extracellular environment (Fig. 8) [127-130]. There are at least 50 distinct proteins known to be involved in FACs. Actin [131], vinculin, talin, tensin, a-actinin, and filamin provide a structural role, while focal adhesion kinase [132], integrin-linked kinase, Src-family kinase, PINCH, paxillin... 

---