A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway.
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.
Kouhara
H
H
Department of Pharmacology, New York University Medical Center, New York 10016, USA.
Hadari
Y R
YR
Spivak-Kroizman
T
T
Schilling
J
J
Bar-Sagi
D
D
Lax
I
I
Schlessinger
J
J
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D003001:Cloning, Molecular; D051380:GRB2 Adaptor Protein; D050356:Lipid Metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000302:isolation & purification* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D016716:PC12 Cells; D010750:Phosphoproteins / Q000235:genetics / Q000302:isolation & purification* / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D017421:Sequence Analysis; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C106534:FRS2 protein, human; D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; C495950:Grb2 protein, rat; D008565:Membrane Proteins; D010750:Phosphoproteins; D011506:Proteins; D017468:Receptors, Fibroblast Growth Factor; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D018631:ras Proteins