Navigation Links
Same protein that fires up cancer-promoting Erk also blocks its activation

HOUSTON A protein which is intimately involved in cancer-promoting cell signaling also keeps a key component of the signaling pathway tied down and inactive, a team led by scientists from The University of Texas MD Anderson Cancer Center reports this week in Nature Structural Molecular Biology.

Shc, pronounced "schick," plays a key role in activating signals which lead to cell proliferation (and cancer) when cells are stimulated, however it unexpectedly turns out to be a tumor-suppressor, keeping Erk under wraps when a cell is less active, said senior author John Ladbury, Ph.D., professor in MD Anderson's Department of Biochemistry and Molecular Biology.

"Shc is a checkpoint to prevent out of control cell growth, binding to Erk when a cell is not being stimulated by growth factors," Ladbury said. "Otherwise, the lower-level background signaling that's always present in a cell would be uncontrolled."

Keeping Erk in check while the cell idles

Overexpression of Erk occurs in many types of cancer, including ovarian and prostate cancer and Hodgkin lymphoma, so cellular control of its activity is important.

In the absence of external stimulation by growth factors, cells remain active but lower levels of cell signaling occur, which Ladbury compares to a car idling, ready to roll. Under these conditions control mechanisms are in place to prevent the cell kicking into gear. Shc turns out to be one of these controllers.

"We're essentially looking at the cell in a resting, but ready, state," Ladbury said. "I would argue that's probably more like a cell behaves in tissue, it's not normally getting a slug of growth factors as is often the way when we investigate signaling in experiments in the lab. There's still a lot going on in the cell, basically background activity."

These findings point to a number of therapeutic possibilities, including the measurement of Shc concentration levels as a diagnostic tool and of finding small molecule drugs that block growth-factor signaling to Shc, keeping it bound to Erk, Ladbury noted.

Growth factors provide double boost for Erk

When the appropriate growth factor receptor is stimulated Erk is activated in the MAP Kinase pathway. It dives into the cell nucleus and turns on a variety of genes, actions that contribute to cancer proliferation, blood vessel production and metastasis when signaling is out of control.

When receptor tyrosine kinases on the cell surface connect with growth factors, they normally send a signal via Shc that sets off a chain of actions leading to Erk activation. Ladbury and colleagues looked at Shc's connections to epidermal growth factor receptor (EGFR) signaling.

The team found in mammalian cell lines that:

  • Under non-stimulated conditions Shc binds to Erk in the cell cytoplasm at binding sites that are unique on both proteins.
  • Stimulation via EGFR reduces this connection, but not by competing with Shc at the Shc-Erk binding site.
  • Instead, on stimulation from outside the cells, EGFR adds phosphate groups to itself at specific sites. One of these forms a binding for Shc, which distorts the protein's shape, making it impossible for Erk to bind.
  • Overexpression of Shc decreases the amount of activated Erk, because Shc mops up free Erk molecules.
  • Depleting Shc expression with short hairpin RNA resulted in higher levels of activated Erk.
  • When separated from Shc, Erk moves into the nucleus and activates genes even when the cell is not receiving a stimulus. Thus without the controlling influence of Shc, Erk can run riot in the cell giving rise to unrestrained cell reproduction.

Shc-Erk connection confirmed

Ladbury and colleagues then tested their results in the C.Elegans, a worm model frequently employed in biological research. Both Shc and Erk are greatly similar between humans and the worms.

Experiments showed that Shc blocks Erk function by sequestering it away from the Ras-Raf-Mek MAPK pathway in the worms. Without the Shc-Erk connection, the MAPK pathway is activated, causing excessive Erk activation.

EGFR stimulation not only sets off the normal activation of Erk via Shc and the MAPK pathway, Ladbury said, but also frees Erk for greater availability for activation by breaking the tie to Shc.

Co-authors with Ladbury are first author Kin Man Suen and Chi-Chuan Lin, Ph.D., Fernando Melo, Ph.D., Zamal Ahmed, Ph.D., and Stefan Arold, Ph.D., all of MD Anderson's Department of Biochemistry and Molecular Biology; Roger George, Ph.D., of the London Research Institute of Cancer Research UK; Eleanor Biggs, of the University of Bath, Bath, UK; and Melanie Drake and Swathi Arur, Ph.D., of MD Anderson's Department of Genetics.

Suen is a graduate student in The University of Texas Graduate School of Biomedical Sciences, which is run jointly by MD Anderson and The University of Texas Health Science Center at Houston. Ladbury and Arold also are affiliated with the Center for Biomolecular Structure and Function at MD Anderson.


Contact: Scott Merville
University of Texas M. D. Anderson Cancer Center

Related medicine news :

1. Warwick scientists uncover how checkpoint proteins bind chromosomes
2. Specific protein triggers changes in neurons in brain reward center linked to cocaine addiction
3. Unusual protein helps regulate key cell communication pathway
4. Protein prevents DNA damage in the developing brain and might serve as a tumor suppressor
5. RANK protein promotes the initiation, progression and metastasis of human breast cancer
6. Protein may represent a switch to turn off B cell lymphoma
7. Protein RAL associated with aggressive characteristics in prostate, bladder and skin cancers
8. Breast cancer clinical trial tests combo of heat shock protein inhibitor and hormonal therapy
9. Pivotal role for proteins -- from helping turn carbs into energy to causing devastating disease
10. New molecular structure offers first picture of a protein family vital to human health
11. Wayne State University researcher examines proteins role in diabetic retinopathy
Post Your Comments:
(Date:11/25/2015)... ... November 25, 2015 , ... On November 10, 2015, Bohrer Brady, ... of Connecticut on behalf of a home health care worker who provided companionship services ... home health care workers employed by Humana, Inc., Humana at Home, Inc., and SeniorBridge ...
(Date:11/25/2015)... Canadian, OK (PRWEB) , ... November 25, 2015 , ... ... and International training center for the Narconon network, announced the release of a new ... Since 1966 the Narconon organization has been working with drug- and alcohol-addicted individuals with ...
(Date:11/25/2015)... , ... November 25, 2015 , ... ... double board certified facial plastic surgeon specializing in both surgical and non-surgical treatments, ... The Skin Spa at Hobgood Facial Plastic Surgery. , Highly trained and ...
(Date:11/25/2015)... ... ... Today, Mothers Against Drunk Driving (MADD) learned that the number ... first time since 2011. In 2014, there were 9,967 fatalities involving an alcohol impaired ... Highway Traffic Safety Administration (NHTSA), 32,675 people were killed in traffic crashes in 2014. ...
(Date:11/25/2015)... ... ... An unlikely combination of recycled plastic shopping bags in ... to have a more dignified and comfortable night’s sleep. , Residents of Friendship ... bags into sleeping mats for the homeless. The project, according to Jeannette ...
Breaking Medicine News(10 mins):
(Date:11/25/2015)... - Will Also Offer Point -of- ... --> - Will Also Offer Point ... --> - Will Also Offer ... (CME) Elsevier , a world-leading provider of ... diagnostic imaging textbooks and decision support tools, as well as prominent ...
(Date:11/24/2015)... , November 25, 2015 ... due to repeated failure of IVF cycles. After failure ... was totally dejected and had lost all hopes that she would be able ... Indian miracle child conceived after failure of over 15 ... abroad (UK) before they decided to take one last attempt with ...
(Date:11/24/2015)... Nov. 24, 2015  Array BioPharma Inc. (Nasdaq: ... Executive Officer, Ron Squarer , will present ... New York.  The public is welcome to participate ... Array BioPharma website.Event:Piper Jaffray Annual Healthcare ConferencePresenter:  , ... 2, 2015Time:1:30 p.m. Eastern Time Webcast: ...
Breaking Medicine Technology: