Non-receptor tyrosine kinases or non-specific protein-tyrosine kinases are enzymes that can transfer a phosphate group from ATP to a tyrosine residue in a protein. Non-receptor tyrosine kinases are a subgroup of the larger class of tyrosine kinases. Phosphorylation of proteins by kinases is an important mechanism in signal transduction for regulation of enzyme activity.
In humans, there are 32 cytoplasmic protein tyrosine kinases (EC 188.8.131.52).
The first non-receptor tyrosine kinase identified was the v-src oncogenic protein. Most animal cells contain one or more members of the Src family of tyrosine kinases.
A chicken sarcoma virus was found to carry mutated versions of the normal cellular Src gene.
The mutated v-src gene has lost the normal built-in inhibition of enzyme activity that is characteristic of cellular SRC (c-src) genes. SRC family members have been found to regulate many cellular processes.
For example, the T-cell antigen receptor leads to intracellular signalling by activation of Lck and Fyn, two proteins that are structurally similar to Src.
SRC family kinases are nonreceptor, or cytoplasmic, protein tyrosine kinases. They were initially characterized in the context of cell growth and differentiation; more recently, however, their roles in such diverse processes as cell adhesion and motility, carcinogenesis, immune cell function, and even learning and memory, have been appreciated (135). In addition to SRC itself, there are eight other members of the SRC family including YES, FYN, FGR, BLK, LCK, HCK, LYN, and YRK; together they comprise the largest family of nonreceptor protein tyrosine kinases (51). SRC, FYN, and YES are ubiquitously expressed,
Overview of SRC family kinase (SFK) structure showing numbered SRC homology (SH) domains. Chicken (c)-Src is shown (top); by convention, important residues in SFKs are numbered in accordance with homology to this prototypical kinase. SH1 is the catalytic or kinase domain. An essential regulatory tyrosine in the middle of this domain is shown (Y416; red), phosphorylation of which is required for full activation of the kinase. Phosphorylation of the COOH terminal regulatory tyrosine (Y527; also shown in red) promotes intramolecular interaction with the upstream SH2 domain (red arrow); dephosphorylation of this tyrosine eliminates the interaction and renders the kinase domain accessible and active. The chicken viral (v)-Src proto-oncogene (bottom) lacks the COOH terminal inhibitory Y527 and is therefore constitutively active, accounting for its transforming potential.
SRC is activated by one of several possible mechanisms. Integrin-dependent sensing of cell membrane tension is well supported experimentally. SRC may also be activated via the EGFR, via a putative tonicity-responsive G protein coupled receptor (GPCR) or via another mechanism. The MAPK, p38, which functions in concert with SFKs in the hypertonicity response, is indirectly activated by this stressor; the upstream kinase elements in the p38 MAPK module are not shown. Of note, the ultimate sensor of hypertonicity in the p38 pathway has not been identified. Activation of SRC or a related SFK influences phosphorylation of ion transport effectors, including the epithelial sodium channel (ENaC) and isoforms of Na+/H+ exchanger (NHE), Na+-K+-Cl– cotransporter (NKCC), and Kv. Modulation of a subset of these transport pathways achieves RVI. Stress-dependent transactivation of the EGFR requires cleavage of the HB-EGF ectodomain. This process requires activation of SRC and p38.