Inhibition of basal FGF receptor signaling by dimeric Grb2.
Receptor tyrosine kinase activity is known to occur in the absence of extracellular stimuli. Importantly, this "background" level of receptor phosphorylation is insufficient to effect a downstream response, suggesting that strict controls are present and prohibit full activation. Here a mechanism is described in which control of FGFR2 activation is provided by the adaptor protein Grb2. Dimeric Grb2 binds to the C termini of two FGFR2 molecules. This heterotetramer is capable of a low-level receptor transphosphorylation, but C-terminal phosphorylation and recruitment of signaling proteins are sterically hindered. Upon stimulation, FGFR2 phosphorylates tyrosine residues on Grb2, promoting dissociation from the receptor and allowing full activation of downstream signaling. These observations establish a role for Grb2 as an active regulator of RTK signaling.
Department of Biochemistry and Molecular Biology and Center for Biomolecular Structure and Function, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Chi-Chuan
CC
Lin
Fernando A
FA
Melo
Ragini
R
Ghosh
Kin M
KM
Suen
Loren J
LJ
Stagg
John
J
Kirkpatrick
Stefan T
ST
Arold
Zamal
Z
Ahmed
John E
JE
Ladbury
D019281:Dimerization; D051380:GRB2 Adaptor Protein / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D010766:Phosphorylation; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction
D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2