Src family kinases (SFKs) are key factors in the process of coupling signals from the cell surface to intracellular machinery and have been attracting great interest and the efforts of scientists for over a century.
Nine members of this family have been identified to date, including Src, Fyn, Lck, Lyn and Yes, which are highly expressed in neural cells. All the members share a common topology. The catalytic Src homology (SH) 1 domain (catalytic domain) is located near the C-terminus and contains an activation loop with an important tyrosine residue, Y416 in chicken cellular Src (c-Src). This tyrosine can be autophosophorylated when SFKs are in an open conformation, which subsequently upregulates SFK activity. The N-terminus of the catalytic domain links to an SH2 domain followed by an SH3 domain. The SH2 domain has a strong binding affinity for phosphorylated tyrosine residues and the SH3 domain binds to proline-rich motifs. An SH3-domain-binding ligand exists between the catalytic and SH2 domains and is thought to participate in intramolecular interaction which may be involved in SFK inactivation. Phosphorylation of Y416 disrupts this interaction, further aiding in the activation of SFKs. The C-terminal tail of SFKs contain a regulatory tyrosine, Y527 in chicken c-Src. This tyrosine, when phosphorylated, acts as an SH2 domain ligand. Binding of the SH2 domain to the phosphorylated Y527 is thought to lock the SFK in an inactive conformation. At the N-terminus of SFK is an SH4 domain which is involved in anchoring the protein to the membrane through myristoylation or palmitoylation. Each SFK member also contains a unique region between the SH3 and SH4 domains.
Three types of Src have been identified: cellular (c-Src), viral (v-Src) and neuronal (n-Src). v-Src lacks the C-terminal regulatory region and is consequently constitutively active. n-Src contains a 6–17 amino acid insertion in the SH3 domain and is the dominant form expressed in neurons. SFKs expressed in the nervous system are found to be critically involved in the regulation of many neural functions mediated through growth factors, G-protein-coupled receptors or ligand-gated ion channels. As such, SFKs have become important targets for therapeutic research to treat disease states in the nervous system.
The three minireviews in this series focus on recent findings dealing with SFK regulation and function in the nervous system. The first minireview by Salter and colleagues focuses on the discovery of the Src regulation of N-methyl-d-aspartate (NMDA) receptors in pain and schizophrenia. The second minireview by MacDonald and colleagues focuses on the discovery of Fyn signaling in the regulation of NMDA receptors. In the third minireview, Groveman et al. discuss the NMDA receptor-associated SFK signaling complex consisting of SFKs, the SFK activator protein phosphatase alpha, and the SFK inhibitor C-terminal Src kinase, as well as the regulation of stability and activity of n-Src.
[ Bradley R. Groveman obtained his BS in Biochemistry from the State University of New York at Geneseo, USA in 2006. From there, he joined the Biomedical Sciences program at Florida State University to pursue his PhD. Under Dr Xian-Min Yu, he studied the mechanisms of Src kinase regulation and interaction with N-methyl-d-aspartate receptors. He was awarded his PhD in 2011 and is currently a postdoctoral researcher at the National Institute of Health, USA. ]
[ Xian-Min Yu, D.Sc.H, is an Associate Professor in the Department of Biomedical Sciences at Florida State University, USA. He received his doctorate from the University of Heidelberg, Germany in 1989, and worked as a postdoctoral researcher in 1990–1997 and an Assistant Professor in 1998–2004 at the University of Toronto. His research is focused on the regulation of N-methyl-d-aspartate (NMDA) receptors by intracellular signaling. ]