Pharmacology of Src family kinases and therapeutic implications of their modulators

Abstract

Src family kinases (SFKs), the largest family of nonreceptor tyrosine kinases, include 10 members. Src was the first gene product discovered to have intrinsic protein tyrosine kinase activity. Src is widely expressed in many cell types and can have different locations within a cell; the subcellular location of Src can affect its function. Src can associate with cellular membranes, such as the plasma membrane, the perinuclear membrane, and the endosomal membrane. SFKs actions on mammalian cells are pleiotropic and include effect on cell morphology, adhesion, migration, invasion, proliferation, differentiation, and survival. SFKs at one end have been documented to play some important physiological functions; on the other end, they have been described in the pathophysiology of some disorders. In this review article, an exhaustive attempt has been made to unearth pharmacology of SFKs and therapeutic implications of SFKs modulators.

Tyrosine kinase Fyn promotes osteoarthritis by activating the β-catenin pathway

“…PP1 was identified as a high-potency inhibitor of Fyn and acts as a competitive inhibitor of ATP binding. Currently, both AZD0530 and PP1 are mainly under investigation for the treatment of solid tumours, lung cancer and Alzheimer’s disease 32. In this study, we have demonstrated that OA progression can be prevented by targeting Fyn with these two inhibitors.…”

Dasatinib, a Src inhibitor, sensitizes liver metastatic colorectal carcinoma to oxaliplatin in tumors with high levels of phospho-Src

“…In its inactive form, the end carboxyl-terminal Tyr527 residue is phosphorylated by protein tyrosine kinase Csk. Dephosphorylation at this level induces a conformational change in the protein, allowing the autophosphorylation of Tyr at residue 419, which is present in the activation loop, promoting and activating Src kinase (p-Src) [17, 18]. In normal basal conditions, 90-95% of Src es found in its inactive conformation.…”

Ponatinib promotes a G1 cell-cycle arrest of merlin/NF2-deficient human schwann cells

“…Ponatinib did not reduce net levels of ABL phos-phorylation in merlin-deficient HSC (Figure 2A ). Ponatinib induced a dose-dependent increase in the total SRC protein level but did not alter the levels of the other SRC family members, FYN and YES, that play important roles in SC biology as well (Figure 2B ) [ 22 , 23 ]. We found a slight increase in SRC-Tyr416 phosphorylation in merlin-deficient HSC treated with 0.3 to 3μM (with a peak at 1μM).…”