Once considered merely a passive link between proteins that matter, Grb2 - pronounced "grab2" - actually lives up to its nickname with its controlling grip on an important cell signaling pathway, scientists at The University of Texas MD Anderson Cancer Center report in the June 22 issue of Cell.
"Grb2 is a switch that controls normal signaling through the fibroblast growth factor receptor (FGFR)," said the paper's senior author, John Ladbury, Ph.D., professor in MD Anderson's Department of Biochemistry and Molecular Biology.
"Perhaps the best way to think about it is that Grb2 controls cell homeostasis (stable state) before a growth factor binds to FGFR, activating this molecular pathway," Ladbury said.
In addition to discovering a fundamental aspect of FGFR signaling, the researchers' discovery points to a potential explanation of why genomic alterations found in breast, bladder and gastric cancers and melanoma might promote cancer formation and growth, Ladbury noted.
FGFR has a docking station to receive growth factors on the cell surface, and another internal region that passes the growth factor signal on to proteins inside the cell by attaching phosphate groups to them.
FGFR employs phosphorylation to regulate a number of important processes, including the cell cycle, cell proliferation and migration. When some of these pathways become overactive, they can contribute to cancer growth and survival.
Like "a car idling in neutral" ready to go
Grb2's full name reflects its location: growth factor receptor-bound protein 2. In the great rush of molecular signaling pathway mapping in the 1990s, Ladbury noted that Grb2 was labeled an "adaptor protein," one that has no activity of its own apart from connecting to other proteins.
Mapping ran way ahead of figuring out each protein's function in a signaling pathway, Ladbury said, and scientists are still catching 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.