Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling

• Published in: Nature (London) Vol. 363; no. 6424; pp. 85 - 88
• Main Authors: Li, N, Batzer, A, Daly, R, Yajnik, V, Skolnik, E, Chardin, P, Bar-Sagi, D, Margolis, B, Schlessinger, J
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 06.05.1993; Nature Publishing Group
• Subjects: 3T3 Cells; Adaptor Proteins, Signal Transducing; Amino Acid Sequence; Animals; Binding Sites; Biological and medical sciences; Cell physiology; Cells, Cultured; Cellular biology; Epidermal Growth Factor - metabolism; Escherichia coli; Fundamental and applied biological sciences. Psychology; GRB2 Adaptor Protein; GTP-Binding Proteins - metabolism; Humans; Immunologic Techniques; Kidney - cytology; Membrane Proteins - metabolism; Mice; Molecular and cellular biology; Molecular Sequence Data; Protein Binding; Protein-Tyrosine Kinases - metabolism; Proteins; Proteins - metabolism; Receptor, Epidermal Growth Factor - metabolism; Recombinant Fusion Proteins - metabolism; Signal Transduction; Son of Sevenless Proteins; Transfection; Human; Cell culture; Molecular cooperativity; Enzyme; Gene product; Guanine nucleotide; Molecular interaction; Binding site; Molecular exchange; Kidney; Signal transduction; Membrane receptor; Cell line; Second messenger; Onc gene; Protein-tyrosine kinase
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/363085a0

Many of the actions of receptor tyrosine kinases are mediated by the protein Ras, including the activation of various downstream serine/threonine kinases and the stimulation of growth and differentiation. The human protein Grb2 binds to ligand-activated growth factor receptors and downstream effector proteins through its Src-homology (SH) domains SH2 and SH3, respectively, and like its homologue from Caenorhabditis elegans, Sem-5, apparently forms part of a highly conserved pathway by which these receptors can control Ras activity. Here we show that the SH3 domains of Grb2 bind to the carboxy-terminal part of hSos1, the human homologue of the Drosophila guanine-nucleotide-releasing factor for Ras, which is essential for control of Ras activity by epidermal growth factor receptor and sevenless. Moreover, a synthetic 10-amino-acid peptide containing the sequence PPVPPR specifically blocks the interaction. These results indicate that the Grb2/hSos1 complex couples activated EGF receptor to Ras signalling.