GRB2 prevents full activation of FGFR2 signaling in the absence of growth factor binding.

  • Major finding: GRB2 prevents full activation of FGFR2 signaling in the absence of growth factor binding.

  • Mechanism: Inhibition of FGFR is eliminated upon ligand-stimulated phosphorylation of GRB2.

  • Impact: The priming and activation of other RTKs may be similarly controlled by adaptor proteins.

Binding of growth factors to receptor tyrosine kinases (RTK) such as fibroblast growth factor receptor (FGFR) induces dimerization, autophosphorylation, and recruitment of signaling proteins. However, RTKs also undergo a low basal level of priming phosphorylation prior to extracellular stimulation, indicating that control mechanisms prevent full receptor activation. Lin and colleagues report that binding of the adaptor protein growth factor receptor–bound protein 2 (GRB2) to the C-terminus of FGFR2 was necessary and sufficient for basal FGFR2 phosphorylation but inhibited further receptor signaling in the absence of ligand. Structural analysis of the GRB2-FGFR2 complex showed that GRB2 exists as a stable dimer and forms a heterotetrameric complex with 2 molecules of FGFR2 to prime phosphorylation of the receptor. Binding of GRB2 to FGFR2 was disrupted by phosphorylation of tyrosine 209 (Y209) in GRB2, suggesting that this modification releases GRB2 from the receptor to allow for complete FGFR2 activation. Consistent with this idea, FGF9 ligand stimulation induced GRB2 phosphorylation in HEK293T cells, and in vitro kinase experiments showed that the C-terminal SH3 domain of GRB2 was a direct target of FGFR2. Furthermore, substitution of GRB2 Y209 with nonphosphorylatable phenylalanine (Y209F) suppressed ligand-stimulated FGFR2 activation. These results suggest that receptor dimerization by intracellular adaptor proteins may be an important mechanism to prime RTKs for activation and tightly regulate receptor signaling until growth factor stimulation occurs, and that GRB2 may be a suppressor of aberrant RTK activation in tumors.

Lin CC, Melo FA, Ghosh R, Suen KM, Stagg LJ, Kirkpatrick J, et al. Inhibition of basal FGF receptor signaling by dimeric Grb2. Cell 2012;1514–24.

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