The Src family of protein tyrosine kinases (SFKs) plays key roles in regulating signal transduction by a diverse set of cell surface receptors in the context of a variety of cellular environments. SFKs have evolved many ingenious molecular strategies to couple receptors with the cytoplasmic signaling machinery.
An overview of Src
Src tyrosine kinase is composed of c-terminal to n-terminal, including four basic structural domains, namely SH1 (Src Homology 1), SH2, SH3 and SH4, in which SH1 is highly homologous to the first-order structure of Src family catalytic domain. Most Src family proteins have an autonomous phosphorylation site equivalent to Tyr527 at SH1.SH2 is composed of protein components with a length of about 100 amino acid residues, which is relatively conservative and mainly mediates the interconnection of various signal proteins in the cytoplasm to form protein heteropolymer complex, thus regulating signal transmission. SH3 is a conserved amino acid sequence with about 50 amino acid residues. Current studies have found that the recognition site of SH3 is the proline rich region PXXP, which can bind to the target protein through proline with hydrophobic amino terminal residues. SH3 plays a role in subcellular localization and cytoskeletal protein interactions. SH4 is a unique structural domain that connects a saturated 14-alkyl fatty acid.
Inhibitor of Src
There are many kinds of inhibitors of Src family kinase. The following are some commonly used and newest inhibitors：
I Saracatinib is a potent Src inhibitor with IC 50 of 2.7 nM, also inhibits EGFRL861Q (IC50=4nM), EGFRL858R (IC 50= 5nM) and v-Abl (IC 50=30 nM).
IIPP2 is a potent, reversible, ATP-competitive, and selective inhibitor of the Src family of protein tyrosine kinases with IC 50s of 4 and 5 nM for Lck and Fyn, respectively.
III 7-Hydroxychromone is a Src kinase inhibitor with an IC 50 of <300 μM.
IV eCF506 is a highly potent and orally bioavailable inhibitor of the non-receptor tyrosine kinase Src with an IC 50of less than 0.5 nM.
V KB SRC 4 is a potent, and highly selective c-Src inhibitor, with a K i of 44 nM and a K d of 86 nM, and shows no inhibition on c-Abl up to 125 μm; KB SRC 4 has antitumor activity.
VI A 419259 trihydrochloride is a broad-spectrum pyrrolo-pyrimidine inhibitor, designed to enhance selectivity towards the Src family with IC 50 of 9 nM, <3 nM and <3 nM for Src, Lck and Lyn, respectively.
VII 1-Naphthyl PP1(1-NA-PP 1) is a selective inhibitor of Src family kinases v-Src and c-Fyn as well as the tyrosine kinase c-Abl (IC 50 values are 1.0, 0.6, 0.6, 18 and 22 μM for v-Src, c-Fyn, c-Abl, CDK2 and CAMK II respectively).
Src and diseases
A large number of studies have been conducted on the changes and effects of Src family kinases in the process of mitosis in somatic cells, and it has been confirmed that SFKs are involved in the regulation of mitosis. Abnormal expression may be one of the causes of prostate cancer and ovarian cancer, so the study of its inhibitors is particularly important.
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