ReceptorTyrosineKinases-FacultyofScienceatBilkent.ppt

Enzyme-linked Cell Surface Receptors  16 April 2007 Enzyme-linked Cell Surface Receptors Receptor Tyrosine kinases: phosphorylate specific tyrosines Tyrosine kinase associated receptors: associate with intracellular proteins that have tyrosine kinase activity. Receptorlike tyrosine phosphatases: remove phosphate group Receptor Serine/ Threonine kinases: phosphorylate specific Serine/ Threonine Receptor guanylyl cyclases: directly catalyzes the production of cGMP Histidine kinase associated receptors: kinase phoshorylates itself on histidine and then transfers the phosphate to a second intracellular signaling protein. Receptor Tyrosine Kinases (RTKs) Intrinsic tyrosine kinase activity Soluble or membrane-bound ligands: Nerve growth factor, NGF Platelet-derived growth factor, PDGF Fibroblast growth factor, EGF Epidermal growt factor, EGF Insulin Downstream pathway activation: Ras-MAP kinase pathway Functions include: Cell proliferation, differentiation Cell survival Cellular metabolism Some RTKs have been discovered in cancer research Her2, constitutively active form in breast cancer EGF-R overexpression in breast cancer Other RTKs have been uncovered in studies of developmental mutations that block differentiation Outline Activated RTKs transmit signal to Ras protein Ras transduces signal to downstream serine-threonine kinases Ultimate activation of MAP kinase Activation of transcription factors Ligand binding to RTKs Most RTKs are monomeric ligand binding to EC domain induces dimerization FGF binds to heparan sulfate enhancing its binding to receptor: dimeric receptor-ligand complex Some ligands are dimeric: direct dimerization of receptors Insulin receptors occur naturally as a dimer Activation is due to the conformational change of the receptor upon ligand binding Consequences of receptor dimerization Kinase in one subunit P* one or more tyrosine residues on the other Binding of ATP (insulin-R) or protein substrates (FGF-R) Enhanced kinase activity: P* of othe