Negative regulation of immunoreceptor signaling by protein adapters: Shc proteins join the club

Protein adapters couple surface receptors to multiple intracellular signaling modules by acting as scaffolds for the assembly of multimolecular complexes responsible for the coordination and amplification of signals. Through the spatiotemporally controlled recruitment of mediators with opposite activities (e.g. protein tyrosine kinases and phosphatases), adapters are implicated not only in signal initiation and propagation, but also in feedback loops for signal extinction. Moreover, adaptors specialized in preventing or dampening signaling have been more recently discovered. Here we shall present of brief overview of the principal adaptors which act as negative regulators of TCR and BCR signaling, with a focus of the mechanisms underlying this function. We shall then discuss our recent findings implicating p66Shc and Rai, two members of the Shc family of cytosolic protein adapters, in the negative control of antigen receptor signaling, and their role as gatekeepers of autoimmunity and leukemia. © 2010 Federation of European Biochemical Societies.