The protein Grb2, once considered merely a passive link between other proteins, acts as an on-off switch for a critical growth signaling pathway, MD Anderson scientists report this week in the journal Cell..
Grb2, pronounced "Grab2," binds to the fibroblast growth factor receptor (FGFR) to control normal signaling through the FGF pathway, a research team led by John Ladbury, Ph.D., professor in MD Anderson's Department of Biochemistry and Molecular Biology.
In addition to this basic science discovery, the team's findings provide a potential explanation for how genomic changes found in breast, bladder and gastric cancer and melanoma tumors might promote cancer development and progression.
In each case, the portion of the gene that encodes FGFR's internal signaling domain is abnormal, Grb2 binds to the receptor at that spot to control signaling to other proteins.
"If Grb2 can't bind to FGFR there, that could lead to the FGFR pathway being turned on constantly," Ladbury said.
Like "a car idling in neutral" but ready to go
As a receptor tyrosine kinase, FGFR has a docking station to receive growth factors on the cell's surface and an internal domain that relays growth factor signaling on to proteins in the cell by attaching phosphate groups to them.
FGFR employs phosphorylation to regulate a number of important cellular processes, including the cell cycle, cell proliferation and migration. When some of these pathways become overactive, the can contribute to cancer growth and survival.
Ladbury and colleagues found that Grb2 binds to the internal signaling region of FGFR, preventing the receptor from activating other proteins. At the same time, Grb2 binding allows a baseline level of phosphorylation of FGFR that isn't strong enough to initiate signaling by recruiting other proteins.
"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."
They also found when the growth factor FGF docks at the receptor and activates it:
· FGFR then attaches a phosphate group to Grb2.
· 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. The "idling" version of FGFR also is more likely to attract an external growth factor to trigger full signaling.
There's reason to believe this mechanism may apply to other tyrosine kinase receptor proteins, Ladbury noted. Additional research will be required to sort out that possibility.
MD Anderson news release