Cell Signaling

Keeping a Lid on Signaling

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Science  06 Jul 2012:
Vol. 337, Issue 6090, pp. 14
DOI: 10.1126/science.337.6090.14-c

Keeping growth factor receptors turned off when appropriate is just as important as proper activation by ligand binding. This is demonstrated by the developmental abnormalities and cancer-promoting effects ascribed to the uncontrolled activity of such receptors. Lin et al. propose a mechanism by which cells may be protected from unwanted phosphorylation of targets by the fibroblast growth factor receptor (FGFR), a receptor tyrosine kinase. The adaptor protein Grb2 is normally thought to promote receptor signaling by binding to phosphorylated residues on the receptors and interacting with other signaling proteins. In cultured human cells transfected with FGFR, however, Grb2 associated with unstimulated FGFR and was required for a basal amount of autophosphorylation of the receptor. Such basal phosphorylation appeared not to activate signaling, however, because the bound Grb2 sterically inhibited further receptor autophosphorylation. The authors propose that when the receptor becomes stimulated by its ligand, Grb2 itself is phosphorylated by the receptor, resulting in its release and relief of its inhibitory effect on receptor signaling.

Cell 149, 1514 (2012).

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