Resumen de The Docking Protein FRS2alpha Controls a MAP Kinase-Mediated Negative Feedback Mechanism for Signaling by FGF Receptors

B. Lamothe, A. Wong, Irit Lax

• The docking protein FRS2α functions as a major mediator of signaling by FGF and NGF receptors. Here we demonstrate that, in addition to tyrosine phosphorylation, FRS2α 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 FRS2α. Prevention of FRS2α threonine phosphorylation results in constitutive tyrosine phosphorylation of FRS2α in unstimulated cells and enhanced tyrosine phosphorylation of FRS2α, MAPK stimulation, cell migration, and proliferation in FGF-stimulated cells. Expression of an FRS2α 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.