Src Family Kinases Overview
Since the isolation of v-Src as the transforming component of Rous sarcoma virus, and the subsequent identification of its cellular homolog c-Src, there has been intense interest in its activity and regulation. Src is the founding member of a group of non-receptor protein tyrosine kinases termed the Src family kinases (SFKs). All members share a basic mutidomain structure and a high degree of homology. SFKs can be further subdivided into a core group of “typical” SFKs which in humans consists of eight members (Src, Blk, Fgr, Fyn, Hck, Lck, Lyn, and Yes), a small group of atypical members (Brk, Frk and Srm), and two closely related kinases (Csk and Matk), that regulate the typical SFKs.
Typical SFKs are defined by the presence of five domains: a unique region of variable length, containing at its extreme amino-terminus motifs specifying modification by the short fatty acids palmitate and/or myristate; an SH3 domain, which mediates binding to specific PXXP motifs; an SH2 domain which governs binding to specific phosphotyrosine residues; a catalytic domain containing a tyrosine in the activation loop whose phosphorylation modulates catalytic activity; and a short carboxy-terminal tail with a tyrosine residue whose phosphorylation negatively regulates the enzyme. The atypical members all share a similar core structure, although none have the motif required for myristylation, and while Frk and Brk have a regulatory tyrosine in the C-tail, Srm does not. In addition, all atypical members have a nuclear localization sequence in the SH2 domain. The regulators Csk and Matk lack myristylation motifs, activation loop tyrosines and C-terminal regulatory tails.
The activity of typical SFKs is exquisitely regulated by structural constraints. They are usually held in a “closed” inactive form, and transition to an “open” active conformation upon a stimulus. For example, Src in the inactive form is phosphorylated in the C-terminal tail (tyrosine 530), a reaction usually carried out by Csk. This phosphorylation favors interaction between the tail and the SH2 domain which, together with a second intramolecular interaction between the SH3 domain and sequences linking the SH2 domain and the kinase domain, promotes the closed conformation. The SH2 and SH3 domains are masked, and the conformation of the kinase domain is unfavorable for catalysis. Transition to the active state can occur via either dephosphorylation of the tail tyrosine or by the binding of high affinity ligands to the SH2 and/or SH3 domains.
SFKs are frequently activated when extracellular ligands associate with their cognate receptors (such as receptor tyrosine kinases, G-protein coupled receptors, integrin receptors and immune recognition receptors) as well as intrinsically during mitosis. SFKs participate in mitogenesis, cell survival, cytoskeletal reorganization and motility, as well as specialized functions such as immune cell development, neuronal cell signaling, osteoclast and platelet function etc. In addition, deregulation and/or overexpression of both typical and atypical SFKs have been implicated in cancer causation. In keeping with the involvement of SFKs in many signaling pathways, a large and growing number of SFK substrates are being identified (currently more than 50 for Src alone).
Several small molecule inhibitors of SFKs have been identified, of which two (PP2 and SU6656) are generally available. PP2 displays considerable selectivity for SFKs and can inhibit Lck and Fyn in the nanomolar range; however it is an equally potent inhibitor of the PDGF receptor and other RTKs, as well as Tec kinases. SU6656 inhibits SFKs in the high nanomolar range, and does not inhibit the PDGF receptor or Tec, but it is very unlikely to be totally selective for SFKs. Where possible, results obtained with an SFK should be confirmed with a second inhibitor, or using other means.
The Table below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.
References
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