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.

Family Members	Src	Blk	Fgr	Fyn	Hck
Other Names	c-Src pp60c-Src		Src2 p55c-fgr	p59Fyn Slk/Syn	JTK9
Group
Molecular Weight (kDa)	59.8	57.7	59.4	60.7	57.3
Structural Data	536	505	529	537	526
Isoforms	nSrc	Not Known	Not Known	Fyna, Fynb, Fync	p59Hck, p61Hck
Species	Avian (v-Src), human, monkey, mouse, Xenopus, rat, chordite	Human, mouse, rat	Human, mouse, rat	Human, mouse, rat, Xenopus	Human, monkey, mouse, rat
Domain Organization	SH3-SH2-Tyr kinase	SH3-SH2-Tyr kinase	SH3-SH2-Tyr kinase	SH3-SH2-Tyr kinase	SH3-SH2-Tyr kinase
Phosphorylation Sites	Ser12 Ser17 Tyr216 Tyr419 Tyr530	Tyr389 Tyr501	Tyr523 Tyr412	Tyr531 Tyr420	Tyr522 Tyr390
Tissue Expression	Ubiquitous	B cells	Myeloid cells B cells	Ubiquitous	Myeloid cells
Subcellular Organization	Cytoplasm, plasma membrane	Cytoplasm	Cytoplasm	Cytoplasm, plasma membrane	Cytoplasm, plasma membrane
Binding Partners/ Associated Proteins	ADAM12 Csk EGFR FKHR Sam68 Paxillin WASp 14-3-3 β/γ/ε PKCε/ζ	Bcl2 CBL PLCγ2 Ubiquitin protein ligase E3A	CCR3 CD24 SLAM SHIP WASp	PI3K (p85α) Fyn-binding protein SLAM SAP Paxillin	WIP Abl p130Cas
Upstream Activators	ErbB1; AP-1 PDGFR IR AMPK Neu Fibronectin FGR VDR PI3K/Akt/eNOS pathway LPS IFNγ	AML1 BSAP/PAX5 NERF/ELF-2 NFkB BSAP EBF Antigen receptor complex	Negative regulaton of PP1a Chemokine signaling PMN adhesion Urokinase	CD95L NSAIDs RAFTK FAK Vav PDGFR	Actin
Downstream Activation	EGFR Shc Dynamin Clathrin Raf-1 JAK1 STAT1/3/5 Tks5 G protein-linked receptor kinase 2 Caveolin-1	Not Known	PI3K p120/130 Cbl Pyk2 p190RhoGAP Rac	PI3K p120/130 Cbl Pyk2	Ca2+ MAPK
Activators	Growth factors	Not Known	Not Known	Not Known	Not Known
Inhibitors	PP1 PP2 SU6656	Not Known	Not Known	PP1 PP2 SU6656	PP1 PP2
Physiological Function	Cellular proliferation and differentiation, bone remodelling	B lymphoid cell signal transduction	Cellular migration and adhesion	Synaptic plasticity, implicated in learning and memory, cellular growth	May contribute to meutrophil migration and may regulate the degranulation process of neutrophils
Disease Relevance	Embryonic development, multiple cancers, osteoporosis	Some leukemias	B-cell acute lymphoblastic leukemia	Neurological disease – impaired special learning	B-cell acute lymphoblastic leukemia

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