ELSEVIER FEBS Letters 338 (1994) 113-117 FEBS 13565 Minireview The GRB2/Sem-5 adaptor protein Julian Downward* zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQP Imperial Cancer Research Fund, 44 Lincoln’s Inn Fields, London W C2A 3PX, UK Received 13 December 1993 La!! zyxwvutsrqpon LETTERS Abstract GRB2/Sem-5 is a 25-kDa adaptor protein which contains a central Src homology type 2 (SH2) domain flanked by two Src homology type 3 (SH3) domains. GRBUSem-5 was first identified due to the essential role of the sem-5 gene product in the vulva1 induction pathway in Caenorhabditis elegant. The SH2 domain of GRBUSem-5 binds to a number of tyrosine phosphorylated proteins, most notably the epidermal growth factor receptor, the insulin receptor substrate IRS-l and another putative adaptor protein, She. The SH3 domains bind to SOS,a guanine nucleotide exchange factor for Ras proteins. GRB2/Sem-5 brings together SOSand tyrosine phosphoproteins into a complex and thereby may regulate the nucleotide exchange rate of Ras and hence its activation state. Key words: Signal transduction; Adaptor protein; Receptor binding; SH2 and SH3 domains; Activation of RAS zyxwvutsrqponmlkjih 1. Introduction The low molecular weight GTP binding proteins of the Ras family have long been known to play a key role in the regulation of cellular growth and differentiation. They are biologically active when bound to GTP and inactive when bound to GDP. Their activation state in the cell is regulated by the opposing effects of two sets of proteins, the GTPase activating proteins (GAPS) which stimulate the intrinsic rate of hydrolysis of GTP on Ras, and the guanine nucleotide exchange factors that accelerate the replacement of bound GDP with fresh GTP from the cytosol (reviewed in [1,2]). Ras is stimu- lated in whole cells on exposure to a number of growth stimulatory factors. In certain cases these have been shown to activate Ras by suppressing GAP activity [3], but more commonly the activity of guanine nucleotide exchange factors is increased [4-61. Investigation of the mechanisms by which growth factors control the activity of guanine nucleotide exchange factors towards Ras has lead to the identification of GRB2/Sem-5 as a key com- ponent of this pathway. *Corresponding author. Fax: (44) (71) 269 3092. 2. The role of Semd in C. &guns vulva1 development In the nematode worm the genetics of the development of the vulva has been mapped out in some detail. Vulva1 precursor cells carry the Let-23 receptor tyrosine kinase; when this interacts with its ligand, Lin-3, expressed on the surface of the anchor cell, a signal inducing differen- tiation to a vulva1 cell fate is transmitted into the vulva1 precursor cell [7]. A gene, zyxwvutsrqponmlkjihgfedcbaZYXWVU let-60, lying downstream of let-23 on this pathway encodes a worm homologue of Ras [8,9]. More recently, Sem-5 was identified as another component of this pathway, functioning upstream of Ras but downstream of Let-23 [lo] (see Fig. 1). From its sequence, Sem-5 appeared to be an ‘adaptor’ protein, one containing only domains capable of binding other proteins but not having any intrinsic enzymatic activity of its own. Sem-5 is made up of a central Src homology type 2 (SH2) domain, flanked by two Src ho- mology type 3 (SH3) domains. This structure is reminis- cent of Crk, a proto-oncogene product whose function is poorly understood zyxwvutsrqponmlkjihgfedcbaZYXW [l zyxwvutsrqponmlkjihgfedcbaZYXW 11. SH2 domains bind to protein tyrosine phosphorylation sites [12], while SH3 domains bind to proline-rich motifs in proteins [13]. Mutations in Sem-5 that inhibited vulva1 development occurred in res- idues that were highly conserved in the SH2 and SH3 consensus sequences. Although the full significance of these observations was not immediately clear, it was ob- vious that Sem-5 was likely to function to couple a recep- tor tyrosine kinase to an activator of Ras, possibly a 0014-5793/94/%7.00 0 1994 Federation of European Biochemical Societies. All rights reserved. SSDI 0014-5793(93)E1482-2