Gastrin induces tyrosine phosphorylation of Shc proteins and their association with the Grb2/Sos complex.
Gastrin/CCKB G protein-coupled receptors have been shown to mediate proliferative effects of their endogenous ligands. In the present study, we examined the signal transduction mechanisms linked to the G/CCKB receptor occupancy. We report here that gastrin stimulates MAP kinase activation in a dose- and time-dependent manner, a pathway known to play a key role in cell proliferation. We also characterized the molecular events, upstream of p21-Ras, that may link the MAP kinase pathway to G/CCKB receptors. Gastrin induced a rapid and transient increase in tyrosine phosphorylation of several proteins including the 2 isoforms (46 and 52 kDa) of the adaptor protein Shc. Phosphorylated Shc subsequently associated with a complex that includes Grb2 and the p21-Ras activator, Sos. Our results also indicate that Sos becomes phosphorylated in response to gastrin as shown by a reduction in electrophoretic mobility of the protein. Tyrosine phosphorylation of Shc and subsequent complex formation with Grb2 and Sos appear to be a common mechanism by which tyrosine kinase receptors and the G/CCKB G protein-coupled receptor stimulate the Ras-dependent MAP kinase pathway.
INSERM U.151., Institut Louis Bugnard, CHU Rangueil, Toulouse, France.
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Seva
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Kowalski-Chauvel
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Blanchet
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Vaysse
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Pradayrol
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D051380:GRB2 Adaptor Protein; D005755:Gastrins / Q000494:pharmacology*; D007700:Kinetics; D008565:Membrane Proteins / Q000378:metabolism*; D010190:Pancreatic Neoplasms; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D011949:Receptors, Cholecystokinin / Q000502:physiology; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D020664:Son of Sevenless Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D051380:GRB2 Adaptor Protein; D005755:Gastrins; C495950:Grb2 protein, rat; D008565:Membrane Proteins; D011506:Proteins; D011949:Receptors, Cholecystokinin; D055765:Shc Signaling Adaptor Proteins; C528035:Shc1 protein, rat; D020664:Son of Sevenless Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D019000:Phosphotyrosine; D017871:Calcium-Calmodulin-Dependent Protein Kinases