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:
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.
University of Texas M. D. Anderson Cancer Center: http://www.mdanderson.org
This press release was posted to serve as a topic for discussion. Please comment below. We try our best to only post press releases that are associated with peer reviewed scientific literature. Critical discussions of the research are appreciated. If you need help finding a link to the original article, please contact us on twitter or via e-mail.
From flying frogs to deep-sea squid, meet some of the other nosferatu of the animal kingdom
After 50 years of cutting-edge seafloor exploration, the Alvin submersible—renegade deep-sea explorer for the Woods Hole Oceanographic Institute—just got a long-deserved makeover. Alvin is the United States’ only deep-diving manned submersible used for science, so its upgrades will have a serious impact on the discoveries we can pull off in the deep.
Animals took so long to evolve and thrive on Earth because of incredibly low levels of oxygen during a period more than a billion years ago, scientists say.
By combining compounds in just the right mixture, researchers have worked out how to produce the olfactory equivalent of white noise
The pain that scratching causes soothes an itch – but only for a second. As soon as the brain's response to that pain kicks it, it ramps up the itch further
A man's lifelong fear of spiders vanished overnight with the removal of a part of his brain – it gives an insight into where and how our fears are stored
Scientists have been puzzling for years over why some people survive Ebola while many others perish. A new study provides strong evidence that individual genetic differences play a major role in whether people die from the disease.
Zookeepers are keeping an eye on the 120-pound giraffe calf, making sure he's getting all the nutrition he needs. He could make his first appearance in the feeding habitat as soon as next week.
Biologists are reporting signs of a possible zombie apocalypse. Well, at least for the honeybee population. A parasite that has been turning bees on the West Coast into zombie-like creatures has started infecting bees in the East, and biologists are still puzzled as to how it all works.
An innate ability some people have to manipulate their vocal frequency could be the key to sounding charismatic, according to new research.