Src Kinases Proteins

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 Src Kinases Proteins Background

The c-Src family of genes encodes cytoplasmic non-receptor protein tyrosine kinases (PTKs) that do not have an extracellular domain. The Src family members are known to convert the extracellular signals from cytokines and growth factors into activation of intracellular mitogenic, differentiative or anti-apoptotic signaling pathways such as the Ras-Raf-MAPK pathway or the Serine/threonine AKT pathway. Src kinases work by phosphorylating specific set of downstream effector proteins.

The Src family of tyrosine kinases was first identified as transforming genes present in some retroviruses. One of the first viruses shown to cause cancer was the Rous Sarcoma Virus, which encodes for the v-src oncogene. c-src is the cellular, non-transforming homolog of the v-src oncogene found in the acute transforming Rous Sarcoma Virus. The other related RNA tumor viruses encoded the related proteins Yes and Fgr, which belong to the Src family of kinases. These family members have been implicated in a variety of cellular processes. The src gene family consists of nine different members namely, src, fgr, fyn, hck, lek, lyn, yes, blk, and yrk. The fyn gene was identified in 1986 by screening human fibroblast libraries using a fgr probe and was originally named as syn or slk but later was renamed as fyn. The fyn, c-src, c-yes and yrk genes are expressed in a broad range of tissues and cell types while blk, c-fgr, hck, lek and lyn genes are restricted to hematopoietic cell lineages. The fyn gene is found to be expressed in fibroblasts, endothelial cells, lymphocytes, monocytes, T-lymphocytes, keratinocytes, platelets and neurons in specific regions of the central nervous system, including the hippocampus. The c-src gene is ubiquitously expressed, but expressed at high levels in the neurons of the central nervous system, platelets and osteoclasts. The other src family members like c-fgr is expressed myeloid cells and mature B cells while lyn is expressed in myeloid and B lymphocytes and brain.

Structural domains of Src kinases

The Src family members share extensive homology with conserved structural motifs and also regulatory mechanisms. The Src PTKs are composed of six distinct functional regions; the SH4, unique, SH3, SH2, SHI domains and the C-terminal region.

The Src homology (SH) 4 domain, which is a 15 amino acid sequence contains signals for lipid modification of the Src PTKs. The glycine at position 2 is important for the addition of a myristic acid moiety, which is involved in targeting Src PTKs to cellular membranes. In addition the cysteine residues in the SH4 domain, which are present in all the Src family members except for Src and Blk are required for palmitoylation. Palmitoylation is reversible and occurs usually within the first 10 amino acids. Palmitoylation contributes to strengthen the association of the kinase with the membrane and also to concentrate the Src family kinases in subcellular regions like caveolae.

The unique region, following the SH4 domain includes approximately 50 to 80 amino acids that are not conserved among different Src family members. The precise function of the unique domain is still unknown but it has been proposed to be important for mediating interactions with receptors or specific proteins. Sequences in the unique domain of Lck mediate its interaction with two T-cell surface molecules, CD4 and CD8. In Src and Lck, serine and threonine phosphorylation sites have been identified in these unique domains. In Src, threonine at positions 34 and 46 and serine at position 72 is phosphorylated by a cyclin-dependent kinase (Cdc2) and cyclin B complex in the mitotic phase of the cell cycle.

Regulation of Src kinases

The SH2 and SH3 domains of the Src kinases play a key role in the regulation of their catalytic activity. The kinase activity of the Src family kinases is regulated by the phosphorylation of a tyrosine residue at the C-terminus. The SH2 domain interacts with the negative regulatory phosphotyrosine residue at position 528 of c-Fyn and 527 in c-Src and also the adjacent residues in the C-terminal regulatory tail. This Y527 in Src and corresponding tyrosine in other Src family members are tyrosine phosphorylated by the cytoplasmic kinase Csk.

There is evidence that indicates that the loss of the tyrosine 528 or the corresponding tyrosine residues in other Src family kinases, leads to their activation. Targeted disruption of Csk in mice caused constitutive activation of c-Fyn and other Src family kinases. Substitution of Tyrosine-528 in c-Fyn lead to its constitutive activation capable of transforming rodent fibroblasts and substitution of Y527 in c-Src also lead to its constitutive activation. Truncation and replacement of the sequences in the c-terminus of v-Src deleting the Y527 accounts for its oncogenic activation. Analysis of the crystal structures demonstrated that the repression of Src kinases is achieved by mechanisms where binding of the SH2 domain to the phosphorylated Y528 of Fyn (or corresponding tyrosine on other Src family members) would lead to its inactivation by forming a closed conformation where the kinase domain is either covered or distorted. This state of conformation results in a low catalytic activity and prevents the interaction of SH2 and SH3 domains with other proteins. Dephosphorylation of the negative regulatory tyrosine releases the closed conformation to an open conformation thereby leading to increase in catalytic activity and interactions of SH2 and SH3 domains with other proteins. The phosphorylation of tyrosine 417 (c-Fyn) or corresponding tyrosine’s in other Src family members in the catalytic domain stabilizes the protein in its active form and also facilitates its ability to bind to its substrates.