title: Interactions of growth factor receptors with cytoplasmic signaling molecules.
abstract: The first step in the action of many growth factors is to bind to the receptors and to stimulate autophosphorylation of the receptors on tyrosine residues. The receptors then form high-affinity physical complexes with cytoplasmic signaling molecules (Fig. 8). It is not clear whether the function of the complexes is to localize signaling molecules at the plasma membrane or to position the molecules to be favored substrates of the receptor. It is also not necessarily true that each receptor molecule binds more than one signaling molecule at a time. We have shown that each of the signaling molecules that binds to the PDGF receptor recognizes a specific site in the receptor cytoplasmic domain. A phosphotyrosine on the receptor is an important determinant of the interaction with the signaling molecule. However, the specificity of the interaction is determined by the receptor sequence surrounding each phosphotyrosine, especially the sequences on the carboxy-terminal side of the tyrosine. SH2 regions of the signaling molecules appear to bind directly to the specific recognition sequences on the receptor. Thus, the intracellular protein-protein interactions that depend on SH2 domains binding to phosphotyrosine are not as random as we once believed but are part of a highly specific system of interactions between tyrosine-phosphorylated proteins and SH2-containing signaling proteins. A major role of tyrosine kinase appears to be in creating specific recognition sites that bind SH2 domains. By elucidating the specificity of these interactions, we have been able to selectively block some interactions while allowing others to occur.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Howard Hughes Medical Institute, University of California, San Francisco 94143-0724.
authors.forename: L T
authors.initials: LT
authors.lastname: Williams
authors.forename: J A
authors.initials: JA
authors.lastname: Escobedo
authors.forename: W J
authors.initials: WJ
authors.lastname: Fantl
authors.forename: C W
authors.initials: CW
authors.lastname: Turck
authors.forename: A
authors.initials: A
authors.lastname: Klippel
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D003593:Cytoplasm / Q000378:metabolism; D020690:GTPase-Activating Proteins; D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases; D010770:Phosphotransferases / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor; D015398:Signal Transduction / Q000502:physiology
chemical_list: D020690:GTPase-Activating Proteins; D010982:Platelet-Derived Growth Factor; D011506:Proteins; D011956:Receptors, Cell Surface; D010770:Phosphotransferases; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor