[Functional roles of phosphotyrosine adaptor Shc in the brain]

Adaptor molecules (adaptor proteins) have indispensable roles in cellular signaling, essential for cellular proliferation, development and metabolism. Shc (Src homology and collagen homology)-family molecule is a group of adaptor molecules, and indicated to be involved in intracellular phosphotyrosine signaling. Shc family has 4 subtypes, ShcA-ShcD, and there are long and short isoforms in ShcA and ShcC whereas ShcB and ShcD have short isoform only. There are three domains conserved in all Shc-family isoforms: phosphotyrosine-binding (PTB) domain, collagen-homology 1 (CH1) domain and Src-homology 2 (SH2) domain, from the N-terminal to C-terminal. PTB and SH2 domains recognize and bind to phosphotyrosine in other molecules, and CH1 domain is recognized and bind to SH2 domain in Grb2, an adaptor molecule, when the tyrosine residues in the domain are phosphorylated. Expression of ShcA is observed in all tissues except for brain in adult animals, although ShcA mRNA is detected in brain during embryonic days. On the other hand, in adult brain, expressions of ShcB, ShcC, and ShcD are observed. Analysis of single knockout mice (ShcA (neuron specific), ShcB, ShcC) and double knockout mice for ShcB and C indicated essential roles of Shc-family molecules in proliferation and survival of cells in various brain regions as well as synaptic plasticity and higher brain functions such as learning and memory. Studies on multiple-knockout mice of Shc-family molecules may further clarify possible involvements of Shc family in physiological and pathophysiological functions in brain.