FRS2 alpha attenuates FGF receptor signaling by Grb2-mediated recruitment of the ubiquitin ligase Cbl

Andy Wong; Betty Lamothe; Arnold Lee; Joseph Schlessinger; Irit Lax

doi:10.1073/pnas.052138899

FRS2 alpha attenuates FGF receptor signaling by Grb2-mediated recruitment of the ubiquitin ligase Cbl

Proc Natl Acad Sci U S A. 2002 May 14;99(10):6684-9. doi: 10.1073/pnas.052138899. Epub 2002 May 7.

Authors

Andy Wong¹, Betty Lamothe, Arnold Lee, Joseph Schlessinger, Irit Lax

Affiliation

¹ Department of Pharmacology, Sterling Hall of Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.

Abstract

Attenuation of growth factor signaling is essential for the regulation of developmental processes and tissue homeostasis in most organisms. The product of Cbl protooncogene is one such regulator, which functions as an ubiquitin ligase that ubiquitinates and promotes the degradation of a variety of cell signaling proteins. Here, we demonstrate that Grb2 bound to tyrosine-phosphorylated FRS2 alpha forms a ternary complex with Cbl by means of its Src homology 3 domains resulting in the ubiquitination of fibroblast growth factor (FGF) receptor and FRS2 alpha in response to FGF stimulation. These observations highlight the importance of FRS2 alpha in the assembly of both positive (i.e., Sos, phosphatidylinositol 3-kinase) and negative (i.e., Cbl) signaling proteins to mediate a balanced FGF signal transduction. However, the partial inhibition of FGF receptor down-regulation in FRS2 alpha-/- cells indicates that the attenuation of signaling by FGF receptor is regulated by redundant or multiple mechanisms.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3T3 Cells
Adaptor Proteins, Signal Transducing*
Animals
Cell Line
Down-Regulation
GRB2 Adaptor Protein
HeLa Cells
Humans
Ligases / genetics
Ligases / metabolism*
Membrane Proteins / genetics
Membrane Proteins / metabolism*
Mice
PC12 Cells
Phosphoproteins / genetics
Phosphoproteins / metabolism*
Proteins / genetics
Proteins / metabolism*
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism*
Proto-Oncogene Proteins c-cbl
Rats
Receptors, Fibroblast Growth Factor / metabolism*
Signal Transduction*
Ubiquitin / metabolism
Ubiquitin-Protein Ligases
src Homology Domains

Substances

Adaptor Proteins, Signal Transducing
FRS2 protein, human
GRB2 Adaptor Protein
GRB2 protein, human
Grb2 protein, mouse
Grb2 protein, rat
Membrane Proteins
Phosphoproteins
Proteins
Proto-Oncogene Proteins
Receptors, Fibroblast Growth Factor
Ubiquitin
Proto-Oncogene Proteins c-cbl
Ubiquitin-Protein Ligases
Ligases
CBL protein, human
Cbl protein, mouse