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Grb2 holds powerful molecular signaling pathway in check

Public release date: 22-Jun-2012
[ | E-mail | Share ]

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

Protein binds to growth factor receptor, priming it for normal function; Likely tie to 4 cancers

HOUSTON - 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.

"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.

Suen is a graduate student in The University of Texas Graduate School of Biomedical Sciences, a joint program of MD Anderson and The University of Texas Health Science Center at Houston.

---

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AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.

Public release date: 22-Jun-2012
[ | E-mail | Share ]

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

Protein binds to growth factor receptor, priming it for normal function; Likely tie to 4 cancers

HOUSTON - 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.

"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.

Suen is a graduate student in The University of Texas Graduate School of Biomedical Sciences, a joint program of MD Anderson and The University of Texas Health Science Center at Houston.

---

[ | E-mail | Share ]

?

AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert! system.

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FACT CHECK: Romney, Obama on immigration plans

President Barack Obama speaks at The National Association of Latino Elected and Appointed Officials? Annual Conference at the Walt Disney World Resort, Friday, June 22, 2012, in Lake Buena Vista, Fla. (AP Photo/Carolyn Kaster)

President Barack Obama speaks at The National Association of Latino Elected and Appointed Officials? Annual Conference at the Walt Disney World Resort, Friday, June 22, 2012, in Lake Buena Vista, Fla. (AP Photo/Carolyn Kaster)

Republican presidential candidate, former Massachusetts Gov. Mitt Romney, speaks at the NALEO (National Association of Latino Elected and Appointed Officials) conference in Orlando, Fla., Thursday, June 21, 2012. (AP Photo/Charles Dharapak)

President Barack Obama speaks at The National Association of Latino Elected and Appointed Officials? Annual Conference at the Walt Disney World Resort, Friday, June 22, 2012, in Lake Buena Vista, Fla. (AP Photo/Carolyn Kaster)

WASHINGTON (AP) ? President Barack Obama flatly blamed Republicans on Friday for failing to support immigration reforms in the last few years.

But Obama didn't tell the whole story in his speech to the National Association of Latino Elected and Appointed Officials. His own Democratic colleagues had a hand in defeating one immigration bill two years ago.

A day earlier, presumptive GOP presidential nominee Mitt Romney promised in a speech to the same group that he would ease the path to a green card, fix a complicated and cumbersome system to let farm workers into the United States and finish a high-tech fence along the Mexican border. He was glossing over how difficult some of those changes could be. Some already have been tried, with little or no success.

Here's a closer look at Obama's statement, Romney's assertions and how they match up with the facts:

OBAMA: "We should have passed the DREAM Act a long time ago. It was written by members of both parties. When it came up for a vote a year and a half ago, Republicans in Congress blocked it. The bill hadn't changed. The need hadn't changed. The only thing that had changed was politics."

THE FACTS: Five Senate Democrats voted against sending the DREAM Act to the Senate floor for full consideration. The bill would have created a path to citizenship for many young illegal immigrants brought to the United States as children. Last week, Obama announced plans to stop deporting illegal immigrants who would have qualified for the DREAM Act. The policy change does not include a path to citizenship.

ROMNEY: "As president, I'd reallocate green cards to those seeking to keep their families under one roof. And we will exempt from caps the spouses and minor children of legal permanent residents. And we will eliminate other forms of bureaucratic red tape that keep families from being together." He added: "And if you get an advanced degree here, we want you to stay here. So I'd staple a green card to the diploma of someone who gets an advanced degree in America."

THE FACTS: It's unclear whether Romney would have the authority if elected president to change the way green cards are issued, or whether he would need help from Congress. It is Congress that sets the annual limits for visas for foreigners who have advanced degrees in certain fields of science, math and other professions. Lately, Republicans and groups representing U.S. workers have blocked legislative attempts to increase those limits.

Advocates for immigration reform have long argued that the president can use executive powers to relax or change various immigration regulations. President Barack Obama has done that twice in the last year. First, he allowed prosecutors discretion to focus deportation of illegal immigrants on those with a criminal record or who otherwise pose a threat. Last week, he announced plans to stop deporting many young illegal immigrants brought to the United States as children who have not committed a crime in the U.S. and to grant them work permits.

Republicans have argued that Obama stretched his authority, but Romney seems to be suggesting he, too, could act alone to make broad changes.

And Romney's proposal for keeping educated foreigners in the U.S. isn't original. Obama, in a May 2011 immigration proposal, called for "encouraging foreign students to stay in the U.S. and contribute to our economy by stapling a green card to the diplomas" of those with advanced science, technology, engineering and math degrees.

ROMNEY: "I will work with states and employers to update our temporary worker visa program so that it meets our economic needs."

THE FACTS: Temporary and seasonal workers are considered a necessity for the U.S. agriculture industry, but importing legal workers has proved difficult. The Labor Department's visa program for temporary seasonal workers has long been viewed as costly, cumbersome and inefficient.

Several attempts to overhaul it that included a path to legalization for the workers have been blocked in Congress. Republicans have repeatedly said that any immigration bill offering a path to legalization would not win their support.

ROMNEY: "We should field enough Border Patrol agents, complete a high-tech fence and implement an improved exit verification system."

THE FACTS: Romney's plans don't take notice of what's already been done, including record-high staffing levels along the border and the failure of a Bush-era virtual fence plan.

The Border Patrol has more than 18,500 agents working on the southern border. In the year budget ending last September, agents apprehended about 340,000 illegal immigrants, the fewest in nearly 40 years ? an average of 18 apprehensions per agent. The decrease in apprehensions has been linked to a weak economy producing fewer jobs in the U.S. and to more law enforcement agents and technology being deployed along the border.

Under the Bush administration, the government built hundreds of miles of fencing along the Mexican border. A planned virtual fence was also started, but then scrapped by the Obama administration in 2010 after the project was deemed a failure. About 53 miles of virtual fencing is in place, at a cost of about $1 billion.

An exit verification system has been sought since after the Sept. 11, 2001, terrorist attacks, but efforts to build one have been repeatedly stymied, most often because of the projected costs. Earlier this year, John Cohen, deputy counterterrorism coordinator for the Homeland Security Department, told a congressional panel that the agency was finalizing plans for a biometric data system to track who leaves the country and when. He didn't give details.

___

Associated Press writer Suzanne Gamboa contributed to this report.

___

Follow Alicia A. Caldwell on Twitter at www.twitte.com/acaldwellap

Associated Press

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Justin Bieber: Number-One Around the World!

This just in: Justin Bieber is very popular.

Within a day of the 18-year old singer releasing his latest studio album, "Believe" ranks first on the iTunes Top Albums chart in the United States, Spain, New Zealand, Belgium, Finland... and you get the idea.

In all, the Biebs sits atop this chart in a whopping 34 countries! We now have proof: Justin is popular "All Around the World."

Justin Bieber Album Preview

There's little doubt that Justin will take over number-one on next week's Billboard 200, as well, which tracks number of album copies sold in seven days. But that's where things could get awkward:

Usher is at the top of that chart at the moment. Sorry, mentor. You're gonna have to make room for your protege.

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Design and Implementation of Intelligent Management Integration ...

Abstract URL:http://www.it-paper.com/design-and-implementation-of-intelligent-management-integration-for-transmitter-room-7.html

This subject stems from Shandong TV Station,and this project is set up by the Office of Science and Technology of Shandong Province, and pass through the Identification of the office.This paper provides the overall Intelligent integration-manage design of the room for transmitting,and based on this,supply software and hardware design of the project,this paper provides details of the system structure, working principle,hardware structure and software control strategy and programming method,and completed the installation,commissioning and trial operation.The system uses computer technology,network technology,communications technology,automatic control technology etc on the transmitter remote control,remote,remote testing.With features of the hills and the foot of the mountain cable communications, GPS automatic schools,fault alarm by sending SMS automatically. Supporting LAN and Internet dual-network interconnectivity,and taking effective mining,anti-electromagnetic interference measures. Achieving integration of real-time monitoring of the transmitter, television signal control and security.Using MCGS configuration software to develop a local server monitoring program, CX-Programmer5.0 to develop PLC Software.Even in the case without the local server PLC can work as usual.Controller Link cable network has the advantage of convenience installation,high speed communication,Security and reliability.Modular structure of the system aids maintenance,debugging and system upgrade.The result shows that the system has excellent performance,friendly interface and it is easy to use,and it create a technological conditions for the transmitter to achieve? Unattended,it was staying?.It has high practical values and Promote values.

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Music mogul Russell Simmons urges peace in Israel

AAA??Jun. 21, 2012?2:38 PM ET
Music mogul Russell Simmons urges peace in Israel
By BLAKE SOBCZAKBy BLAKE SOBCZAK, Associated Press??

Hip hop mogul Russell Simmons, second left, looks on as US Rabbi Marc Schneier president and founder of the Foundation for Ethnic Understanding (FFEU), second right, and the Western Wall rabbi, Shmuel Rabinovich, right, touch stones of the Western Wall, the holiest site where Jews can pray, in Jerusalem's Old City, Thursday, June 21, 2012. The cofounder of the pioneering Def Jam Recordings record label, which has represented such artists like the Beastie Boys, Jay-Z, Lady Gaga, Jennifer Lopez, LL Cool J and Kanye West, is in Israel on the invitation of Israeli President Shimon Peres.(AP Photo/Blake Sobczak)

Hip hop mogul Russell Simmons, second left, looks on as US Rabbi Marc Schneier president and founder of the Foundation for Ethnic Understanding (FFEU), second right, and the Western Wall rabbi, Shmuel Rabinovich, right, touch stones of the Western Wall, the holiest site where Jews can pray, in Jerusalem's Old City, Thursday, June 21, 2012. The cofounder of the pioneering Def Jam Recordings record label, which has represented such artists like the Beastie Boys, Jay-Z, Lady Gaga, Jennifer Lopez, LL Cool J and Kanye West, is in Israel on the invitation of Israeli President Shimon Peres.(AP Photo/Blake Sobczak)

Hip hop mogul Russell Simmons kisses the stones of the Western Wall, the holiest site where Jews can pray, in Jerusalem's Old City, Thursday, June 21, 2012. The cofounder of the pioneering Def Jam Recordings record label, which has represented such artists like the Beastie Boys, Jay-Z, Lady Gaga, Jennifer Lopez, LL Cool J and Kanye West, is in Israel on the invitation of Israeli President Shimon Peres.(AP Photo/Blake Sobczak)

To hip hop and fashion mogul Russell Simmons, the Israeli-Palestinian conflict is like "a rap beef" that can be resolved through dialogue and understanding.

"A little trust, and it's over," he said.

The cofounder of the pioneering Def Jam Recordings record label, which has represented such artists like the Beastie Boys, Jay-Z, Lady Gaga, Jennifer Lopez, LL Cool J and Kanye West, is in Israel on the invitation of Israeli President Shimon Peres.

When he isn't managing his clothing line Phat Farm or promoting artists, Simmons champions an eclectic mix of causes, from veganism to gay rights to yoga.

In Israel, he's focusing on interfaith trust. He said creating dialogue should be as simple as a mediating a rap battle, were it not for the political deadlock between Palestinians and Israelis.

Muslims and Jews "have the same aspirations and goals that are much greater than the things they call differences," Simmons said.

Simmons is one of the wealthiest figures in hip hop, with a net worth reportedly totaling at least $340 million.

He was one of the first players in the burgeoning hip hop scene in the 1980s. His younger brother is Rev. Joseph Simmons ("Run" of Run-DMC).

Simmons arrived in Israel on behalf of a foundation that aims to promote face-to-face dialogue between ethnic and religious communities. He discussed yoga with the Grand Mufti of Jerusalem, Muhammad Ahmed Hussein, and received a blessing from the rabbi of the Western Wall, Shmuel Rabinowitz.

Simmons even did a headstand in front of the Dome of the Rock, one of the holiest sites to Muslims, though he said it was "for the kids" and not for any yogic spiritual reason.

Associated Press
People, Places and Companies: Jay-Z, Lady Gaga, Jennifer Lopez, LL Cool J, Kanye West, Shimon Peres, Rev Run, Russell Simmons, Palestinian territories, Israel

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Apple posts new iPad ad

Ham in the Fridge, those responsible for the well received if a bit disturbing 5 Minutes to Kill (Yourself), have been up to something. They?ve been lurking in the shadows, left to their own devices, doing something altogether unseemly. They?ve been Bumpin? Uglies. I?ve recently had the chance to talk a bit with Brett Hummel (Creative Director)... | Read more ?

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