A Lipid-Anchored Grb2-Binding Protein That Links FGF-Receptor Activation to the Ras/MAPK Signaling Pathway

TLDR

Activation of the Ras/MAPK cascade is essential for growth factor–induced cell proliferation and differentiation, and the lipid‑anchored protein FRS2 targets signaling molecules to the plasma membrane upon FGF stimulation to link receptor activation with MAPK and other growth‑related pathways. The authors purified, cloned, and characterized FRS2, demonstrating that it is tyrosine‑phosphorylated and recruits Grb2/Sos upon FGF or NGF stimulation. FRS2 is myristylated, a modification essential for its membrane localization, tyrosine phosphorylation, Grb2/Sos recruitment, and MAPK activation, and it is closely related to, and likely identical with, the previously elusive SNT protein.

Abstract

Activation of the Ras/MAPK signaling cascade is essential for growth factor–induced cell proliferation and differentiation. In this report, we describe the purification, cloning, and characterization of a novel protein, designated FRS2, that is tyrosine phosphorylated and binds to Grb2/Sos in response to FGF or NGF stimulation. We find that FRS2 is myristylated and that this modification is essential for membrane localization, tyrosine phosphorylation, Grb2/Sos recruitment, and MAPK activation. FRS2 functions as a lipid-anchored docking protein that targets signaling molecules to the plasma membrane in response to FGF stimulation to link receptor activation with the MAPK and other signaling pathways essential for cell growth and differentiation. Finally, we demonstrate that FRS2 is closely related and probably indentical to SNT, the long-sought target of FGF and NGF receptors.