Molecular Mechanism for the Shp-2 Tyrosine Phosphatase Function in Promoting Growth Factor Stimulation of Erk Activity

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We have previously shown that activation of signal-regulated kinase (Erk) by () treatment was significantly decreased in fibroblast cells expressing a mutant -2 molecule lacking 65 amino acids in the -N domain, -2(Delta46-110). To address the molecular mechanism for the positive role of -2 in mediating Erk induction, we evaluated the activation of signaling components upstream of Erk in -2 mutant cells. -stimulated , , and Mek activation was significantly attenuated in -2 mutant cells, suggesting that -2 acts to promote activation or to suppress the down-regulation of activated . Biochemical analyses indicate that upon stimulation, -2 is recruited into a multiprotein complex assembled on the docking molecule and that -2 seems to exert its biological function by specifically dephosphorylating an unidentified molecule of 90 kDa in the complex. The mutant -2(Delta46-110) molecule failed to participate in the -organized complex for of , correlating with a defective activation of the --Mek-Erk cascade in -treated -2 mutant cells. Evidence is also presented that -2 does not appear to modulate the signal relay from receptor to through the , , and proteins. These results begin to elucidate the mechanism of -2 function downstream of a receptor tyrosine kinase to promote the activation of the -Erk pathway, with potential therapeutic applications in treatment.

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Cell Line Animals Mice Multiprotein Complexes Epidermal Growth Factor ras Proteins Mitogen-Activated Protein Kinases Intracellular Signaling Peptides and Proteins Signal Transduction MAP Kinase Signaling System