Src family

Figure 13.32 Regulation of the catalytic activity of members of the Src family of tyrosine kinases, (a) The inactive form based on structure determinations. Helix aC is in a position and orientation where the catalytically important Glu residue is facing away from the active site. The activation segment has a conformation that through steric contacts blocks the catalytically competent positioning of helix aC. (b) A hypothetical active conformation based on comparisons with the active forms of other similar protein kinases. The linker region is released from SH3, and the activation segment changes its structure to allow helix aC to move and bring the Glu residue into the active site in contact with an important Lys residue.

Sicheri, R, Moarefi, 1., Kuriyan, J. Crystal structure of the Src family tyrosine kinase Hck. Nature 385 602-609, 1997. 

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... 

Suter DM, Forscher P. Transmission of growth cone traction force through apCAM-cytoskeletal linkages is regulated by Src family tyrosine kinase activity. J Cell Biol 2001 155(3) 427-438. 

The nonreceptor PTKs are a large group of signaling proteins that have diverse roles in the control of cell proliferation, differentiation, and death. Some are widely expressed others are restricted to particular tissues. Their early classification was dominated by the discovery of pp60src, to the extent that the major group of kinases were simply known as the Src family. There are at least ten known subfamilies of nonreceptor PTKs. 

In spite of having no intrinsic catalytic domains, activation of T lymphocytes commences with tyrosine phosphorylations, activation of PLC-v with production of IP3 and DAG, and elevation of cytosolic free Ca2+. Thus, the consequences of receptor ligation are not dissimilar from those induced by the receptors for EGF or PDGF. An early study trying to explain the induction of tyrosine kinase activity resulted in the discovery of the nonreceptor protein tyrosine kinase Lck (p56lck), a T-cell-specific member of the Src family. Lck is associated with the cytosolic tail of CD4 (in helper T cells) or CD8 (in cytotoxic T cells) (Figure 8.14). As mentioned, the extracellular domains of these... 

The synthesis of some novel acyclonucleosides involving pyrrolo[2,3-c]pyridazine and a 4-hydroxybutyl side chain has been reported <00H(53)5>. New pyrrolo[2,3-pyrimidines containing an extended 5-substituent, as potent and selective inhibitors of lck (an src-family tyrosine kinase), have been synthesized and tested <00BMCL2171>. 

Nonreceptor protein tyrosine kinases contain a catalytic domain, as well as various regulatory domains important for proper functioning of the enzyme. NRPTKs are found in the inner leaflet of the plasma membrane, cytosol, endosomal membranes and nucleus. These include the Src, Jak, Abl, Tec, Ack, Csk, Fak, Fes, Frk and Syk subfamilies (Fig. 24-3). Since a great deal is known about the structure and regulation of the Src family tyrosine kinase, we will use it to illustrate the principles in NRPTK signaling unique features in other subfamilies will be indicated... 

The unique domain following the SH4 domain from the N-terminus is a region with considerable variation in the amino acid sequences among different Src family members. This unique domain may be involved in protein-protein interactions. For example, the unique region of Lck is linked to CD4 and CD8, while those of Fyn and Lyn may be associated with the T- and B-cell antigen receptors. 

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. 

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