Summary

Adaptor proteins are cytoplasmic signaling molecules that lack intrinsic catalytic activity but they are nevertheless crucial for signal transduction. They bear homology domains (SH2, SH3, PH, PTB, …) important for protein-protein interactions and for function. The first adaptors identified were positive regulators of cell responses, with some even having oncogenic activities. More recently, a new subfamily has emerged that negatively regulates signaling responses. This review will focus on adaptors of this genre and specifically, those that inhibit cytoplasmic tyrosine kinase function and which define a new mechanism for in vivo kinase regulation. They include the inhibitors of the Jak, Syk, Fak and Src kinase family and their mechanism for inhibition as well as their possible function in cellular regulation will be discussed. I. Cytoplasmic protein tyrosine kinases Tyrosine phospshorylation corresponds to less than 0.1 % of the protein phosphorylation content in mammalian cells and yet protein tyrosine kinases play a pivotal role in cell regulation. These enzymes are classified in two distinct families: receptor and non-receptor tyrosine kinases. The first includes receptors for growth factors and ligands involved in neuronal axon guidance. The later comprises cytoplasmic proteins grouped into 8 subfamilies, Src, Fak, Jak, Btk, Syk, Csk