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Grb2 holds powerful molecular signaling pathway in check
Date:6/22/2012

up in that area.

"When you think about it, why would a cell bother to produce a protein that plays only a passive role linking one protein to another?" Ladbury said. He and his colleagues found that's simply not the case with Grb2.

They demonstrated that Grb2 binds to the internal signaling region of FGFR, preventing the receptor from activating other pathways while at the same time allowing a baseline level of phosphorylation of FGFR that isn't strong enough to initiate a signal by recruiting other proteins. This baseline phosphorylation occurs without a growth factor activating the receptor and only happens if Grb2 is bound to FGFR.

"You can think of this like a car that's idling in neutral," Ladbury said. "Its engine is running but it's not going anywhere. "

But it is primed for action, and the team found that this idling version of FGFR is more likely to attract an external growth factor that triggers full signaling. They also found when the growth factor FGF docks at the receptor and activates it:

  • FGFR then attaches a phosphate group to the Grb2 that was holding it in check.

  • Phosphorylated Grb2 disconnects from the receptor.

  • With its internal signaling domain now clear of Grb2, FGFR can change the shape of the domain so it can signal to other proteins by phosphorylating them.

"The growth factor essentially slots that idling car into gear, and off it goes," Ladbury said. Having FGFR warming up before activation appears to be a more efficient way for a cell to activate the pathway than starting from a state of zero phosphorylation.

There's reason to believe this mechanism may apply to other tyrosine kinase receptor proteins, a class of receptors including FGFR that activate signaling cascades by phosphorylating other proteins, Ladbury noted. Additional research will be required to sort out that possibility.

Potential role in cancer suppression


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Contact: Scott Merville
smerville@mdanderson.org
713-792-0661
University of Texas M. D. Anderson Cancer Center
Source:Eurekalert  

Page: 1 2 3

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