The BPS domain of Grb10 inhibits the catalytic activity of the insulin andIGF1 receptors

Grb7, Grb10 and Grb14 comprise a family of adaptor proteins that interact w ith numerous receptor tyrosine kinases upon receptor activation. Between th e pleckstrin homology (PH) domain and the Src homology 2 (SH2) domain of th ese proteins is a region of approximately 50 residues known as the BPS (bet ween PH and SH2) domain. Here we show, using purified recombinant proteins, that the BPS domain of Grb10 directly inhibits substrate phosphorylation b y the activated tyrosine kinase domains of the insulin receptor and the ins ulin-like growth factor I (IGF1) receptor, although inhibition by the BPS d omain is dependent on tyrosine phosphorylation of;he kinase activation loop , peptide competition experiments indicate that the BPS domain does not bin d directly to phosphotyrosine. These studies pro, ide a molecular mechanism by which Grb10 functions as a negative regulator of insulin- and/or IGF1-m ediated signaling, (C) 2001 Published by Elsevier Science B,V, on behalf of the Federation of European Biochemical Societies.