title: Receptor-tyrosine-kinase- and G beta gamma-mediated MAP kinase activation by a common signalling pathway.
abstract: Mitogen-activated protein (MAP) kinases mediate the phosphorylation and activation of nuclear transcription factors that regulate cell growth. MAP kinase activation may result from stimulation of either tyrosine-kinase (RTK) receptors, which possess intrinsic tyrosine kinase activity, or G-protein-coupled receptors (GPCR). RTK-mediated mitogenic signalling involves a series of SH2- and SH3-dependent protein-protein interactions between tyrosine-phosphorylated receptor, Shc, Grb2 and Sos, resulting in Ras-dependent MAP kinase activation. The beta gamma subunits of heterotrimeric G proteins (G beta gamma) also mediate Ras-dependent MAP kinase activation by an as-yet unknown mechanism. Here we demonstrate that activation of MAP kinase by Gi-coupled receptors is preceded by the G beta gamma-mediated tyrosine phosphorylation of Shc, leading to an increased functional association between Shc, Grb2 and Sos. Moreover, disruption of the Shc-Grb2-Sos complex blocks G beta gamma-mediated MAP kinase activation, indicating that G beta gamma does not mediate MAP kinase activation by a direct interaction with Sos. These results indicate that G beta gamma-mediated MAP kinase activation is initiated by a tyrosine phosphorylation event and proceeds by a pathway common to both GPCRs and RTKs.
authors.affiliation: Howard Hughes Medical Institute, Department of Medicine (Cardiology), Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: T
authors.initials: T
authors.lastname: van Biesen
authors.forename: B E
authors.initials: BE
authors.lastname: Hawes
authors.forename: D K
authors.initials: DK
authors.lastname: Luttrell
authors.forename: K M
authors.initials: KM
authors.lastname: Krueger
authors.forename: K
authors.initials: K
authors.lastname: Touhara
authors.forename: E
authors.initials: E
authors.lastname: Porfiri
authors.forename: M
authors.initials: M
authors.lastname: Sakaue
authors.forename: L M
authors.initials: LM
authors.lastname: Luttrell
authors.forename: R J
authors.initials: RJ
authors.lastname: Lefkowitz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D002460:Cell Line; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism; D051380:GRB2 Adaptor Protein; D019204:GTP-Binding Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D020664:Son of Sevenless Proteins; D014443:Tyrosine / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D051380:GRB2 Adaptor Protein; D008565:Membrane Proteins; D011506:Proteins; D011994:Recombinant Proteins; D055765:Shc Signaling Adaptor Proteins; D020664:Son of Sevenless Proteins; D014443:Tyrosine; D004815:Epidermal Growth Factor; D011494:Protein Kinases; D020794:Receptor Protein-Tyrosine Kinases; D019204:GTP-Binding Proteins