The Docking Protein FRS2α Controls a MAP Kinase-Mediated Negative Feedback Mechanism for Signaling by FGF Receptors

Abstract

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.

Bisindolylmaleimide I Suppresses Fibroblast Growth Factor-mediated Activation of Erk MAP Kinase in Chondrocytes by Preventing Shp2 Association with the Frs2 and Gab1 Adaptor Proteins

“…It is well established that Frs2 represents not only the critical mediator of Erk activation in FGF signaling but also a site of negative feedback (56,57). Erk phosphorylates Frs2 on multiple threonine residues, leading to diminished recruitment of Grb2 and down-regulation of Ras/Erk activity (57).…”

“…Erk phosphorylates Frs2 on multiple threonine residues, leading to diminished recruitment of Grb2 and down-regulation of Ras/Erk activity (57). In RCS cells, FGF2 induced rapid, Erk-mediated phosphorylation of the entire Frs2 moiety.…”

Cell-Autonomous and Non–Cell-Autonomous Mechanisms of Transformation by Amplified FGFR1 in Lung Cancer

“…1A and D bottom). Because FRS2 encodes the central adaptor protein downstream of FGFRs ( 15 ), FRS2-amplifi ed lung tumors may depend on signaling downstream of FGF receptors. Overall, FAPP dramatically reduced the number of genes (n Gene ) that occurred in broad amplifi cation peaks ( Fig.…”

“…FGFRs are activated via 22 different FGF ligands resulting in downstream FRS2 and extracellular signal-regulated kinase (ERK) phosphorylation ( 13 ); their signaling is modulated endogenously by multiple negative intrinsic feedback loops (15)(16)(17). Furthermore, alternative splicing of FGF receptors mediates different responses to FGF ligands in epithelial (expressing IIIb splice variants) and mesenchymal tissues (expressing IIIc splice variants) in development ( 18 ).…”

FGFR-1 signaling is involved in spermiogenesis and sperm capacitation

“…It has been shown that Snts localize in the cell membrane through a myristyl anchor and interact with the FGFRs through a phosphotyrosine-binding (PTB) domain (Guy et al, 2002;Kouhara et al, 1997;Xu et al, 1998). Upon FGF stimulation, Snts are phosphorylated on multiple tyrosine residues to provide binding sites for the adaptor protein Grb2 and for the protein tyrosine phosphatase (PTP) Shp2 (Hadari et al, 1998;Kouhara et al, 1997), which in turn leads to the activation of the ERK arm of the mitogen activated protein kinase (MAPK) cascade or the phosphatidylinositol 3-kinase (PI3K) cascade and downstream changes in cell function or phenotype (Gotoh et al, 2004;Lamothe et al, 2004;Lax et al, 2002).…”