The docking protein FRS2alpha controls a MAP kinase-mediated negative feedback mechanism for signaling by FGF receptors.
The docking protein FRS2alpha functions as a major mediator of signaling by FGF and NGF receptors. Here we demonstrate that, in addition to tyrosine phosphorylation, FRS2alpha is phosphorylated by MAP kinase on multiple threonine residues in response to FGF stimulation or by insulin, EGF, and PDGF, extracellular stimuli that do not induce tyrosine phosphorylation of FRS2alpha. Prevention of FRS2alpha threonine phosphorylation results in constitutive tyrosine phosphorylation of FRS2alpha in unstimulated cells and enhanced tyrosine phosphorylation of FRS2alpha, MAPK stimulation, cell migration, and proliferation in FGF-stimulated cells. Expression of an FRS2alpha mutant deficient in MAPK phosphorylation sites induces anchorage-independent cell growth and colony formation in soft agar. These experiments reveal a novel MAPK-mediated, negative feedback mechanism for control of signaling pathways that are dependent on FRS2 and a mechanism for heterologous control of signaling via FGF receptors.
Lax
Irit
I
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
Wong
Andy
A
Lamothe
Betty
B
Lee
Arnold
A
Frost
Adam
A
Hawes
Jessica
J
Schlessinger
Joseph
J
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002448:Cell Adhesion; D002455:Cell Division; D002460:Cell Line; D002465:Cell Movement; D024202:Electrophoretic Mobility Shift Assay; D025461:Feedback, Physiological; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D051380:GRB2 Adaptor Protein; D006801:Humans; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D009154:Mutation; D016716:PC12 Cells; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D010769:Phosphothreonine / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C106534:FRS2 protein, human; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; C495950:Grb2 protein, rat; D008565:Membrane Proteins; D010750:Phosphoproteins; D011506:Proteins; D017468:Receptors, Fibroblast Growth Factor; D010769:Phosphothreonine; D019000:Phosphotyrosine; D005346:Fibroblast Growth Factors; D020929:Mitogen-Activated Protein Kinase Kinases