Featured Research

from universities, journals, and other organizations

Grb2 holds powerful molecular signaling pathway in check

Date:
June 22, 2012
Source:
University of Texas M. D. Anderson Cancer Center
Summary:
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 report.

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.

Related Articles


"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.

"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

Their findings provide a possible mechanism to explain why genomic deletions found in bladder and gastric cancer and point mutations in melanoma might promote those cancers.

In each case, the portion of the gene that encodes FGFR's internal signaling domain is affected. If that domain is abnormal, Grb2 would not be able to bind it."That could lead to the FGFR pathway being turned on constantly," Ladbury said.

FGFR launches the MAPK signaling pathway, which is known to promote cancer when abnormally activated. Ladbury and colleagues have identified a potential tumor-suppressing role for Grb2.

The team developed and confirmed the relationship between Grb2 and FGFR via cell biology experiments, biophysics and structural analysis."I'm extremely proud of this group, which can cover all of those bases and provide a full explanation of a system," Ladbury noted.

The Ladbury group continues to investigate:

  • Whether cancer cells are predisposed to have abnormal levels of Grb2 , which would affect the control of FGFR signaling.
  • How disruption of the cycle of Grb2 binding and release leads to cancer.
  • The mechanism by which Grb2 is phosphorylated by FGFR.

This research was funded by The G. Harold and Leila Y. Mathers Charitable Foundation.

Co-authors are lead author Chi-Chuan Lin, Ph.D., Fernando Melo, Ph.D., Kin Suen, Loren Stagg, Ph.D., Stefan Arold, Ph.D., and Zamal Ahmed, Ph.D., all of MD Anderson's Department of Biochemistry and Molecular Biology and the Center for Biomolecular Structure and Function; and Ragini Ghosh, Ph.D., and John Kirkpatrick, Ph.D., of the Institute of Structural Molecular Biology, University College, London.


Story Source:

The above story is based on materials provided by University of Texas M. D. Anderson Cancer Center. Note: Materials may be edited for content and length.


Journal Reference:

  1. Chi-Chuan Lin, FernandoA. Melo, Ragini Ghosh, KinM. Suen, LorenJ. Stagg, John Kirkpatrick, StefanT. Arold, Zamal Ahmed, JohnE. Ladbury. Inhibition of Basal FGF Receptor Signaling by Dimeric Grb2. Cell, 2012; 149 (7): 1514 DOI: 10.1016/j.cell.2012.04.033

Cite This Page:

University of Texas M. D. Anderson Cancer Center. "Grb2 holds powerful molecular signaling pathway in check." ScienceDaily. ScienceDaily, 22 June 2012. <www.sciencedaily.com/releases/2012/06/120622163858.htm>.
University of Texas M. D. Anderson Cancer Center. (2012, June 22). Grb2 holds powerful molecular signaling pathway in check. ScienceDaily. Retrieved December 17, 2014 from www.sciencedaily.com/releases/2012/06/120622163858.htm
University of Texas M. D. Anderson Cancer Center. "Grb2 holds powerful molecular signaling pathway in check." ScienceDaily. www.sciencedaily.com/releases/2012/06/120622163858.htm (accessed December 17, 2014).

Share This


More From ScienceDaily



More Health & Medicine News

Wednesday, December 17, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

UN: Up to One Million Facing Hunger in Ebola-Hit Countries

UN: Up to One Million Facing Hunger in Ebola-Hit Countries

AFP (Dec. 17, 2014) Border closures, quarantines and crop losses in West African nations battling the Ebola virus could lead to as many as one million people going hungry, UN food agencies said on Wednesday. Duration: 00:52 Video provided by AFP
Powered by NewsLook.com
When You Lose Weight, This Is Where The Fat Goes

When You Lose Weight, This Is Where The Fat Goes

Newsy (Dec. 17, 2014) Can fat disappear into thin air? New research finds that during weight loss, over 80 percent of a person's fat molecules escape through the lungs. Video provided by Newsy
Powered by NewsLook.com
Flu Outbreak Closing Schools in Ohio

Flu Outbreak Closing Schools in Ohio

AP (Dec. 17, 2014) A wave of flu illnesses has forced some Ohio schools to shut down over the past week. State officials confirmed one pediatric flu-related death, a 15-year-old girl in southern Ohio. (Dec. 17) Video provided by AP
Powered by NewsLook.com
Yoga Could Be As Beneficial For The Heart As Walking, Biking

Yoga Could Be As Beneficial For The Heart As Walking, Biking

Newsy (Dec. 17, 2014) Yoga can help your weight, blood pressure, cholesterol and heart just as much as biking and walking does, a new study suggests. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins