From protein signaling to cancer drug development

January 8, 2013 by Angela Herring
Chemical biology professor Carla Mattos studies a protein called RAS, which is important in cell proliferation. Credit: Brooks Canaday

(Medical Xpress)—Living organ­isms depend on pro­teins for their sur­vival. These large, com­plex mol­e­cules mediate nearly every life func­tion, but when the genes that code for them start to mutate, those func­tions begin to break down.

For example, nearly 30 per­cent of all can­cers are medi­ated by muta­tions in a pro­tein called RAS, which is the pri­mary mol­e­cule of interest in the lab of Carla Mattos, a newly appointed pro­fessor of chem­istry in the Col­lege of Sci­ence. Up until now, "RAS has been com­pletely elu­sive as a ," she said.

A member of a larger class of pro­teins called GTPases, RAS pro­motes cel­lular pro­lif­er­a­tion when it is bound to a mol­e­cule called guano­sine triphos­phate, or GTP.

Once bound, RAS can interact with other pro­teins called effector pro­teins, one of which is another three-​​letter pro­tein called RAF. This sets off a cas­cade of other mol­e­c­ular inter­ac­tions that allows the cell to repro­duce itself. This cel­lular pro­lif­er­a­tion doesn't stop until RAS pro­motes the hydrol­ysis of GTP to GDP (guano­sine diphosphate).

For decades, sci­en­tists thought the only way to con­trol this sig­naling process, and sub­se­quently shut down pro­lif­er­a­tion, was through yet another pro­tein called GAP. When bound to RAS, GAP acts like an off switch by speeding up .

But sev­eral mys­teries remained. For one, a genetic muta­tion that makes RAS insen­si­tive to GAP doesn't result in cancer. This is sur­prising because cancer is defined by unchecked cel­lular pro­lif­er­a­tion. In this case, the tra­di­tion­ally under­stood  GAP-​​mediated off switch doesn't work, and yet the process still finds a way to shut down.

Two years ago, Mattos' lab dis­cov­ered a new mech­a­nism for turning off RAS that is medi­ated by some­thing called an "allosteric," or remote, on the pro­tein. When some­thing binds there, RAS' struc­ture changes, including the part that nor­mally inter­acts with GAP.

This new con­for­ma­tion, sta­bi­lized in the pres­ence of RAF and the acti­vated allosteric site, is thought to pro­mote hydrol­ysis of GTP in the absence of GAP and turn off the RAS signal for cell pro­lif­er­a­tion. No one had sus­pected the exis­tence of the alter­nate mech­a­nism until Mattos' results were reported in 2010.

Backed by the sup­port of a new a three–year, $800,000 grant from the National Sci­ence Foun­da­tion, Mattos and mem­bers of her research team will start to tease out the nuances of this alter­na­tive mech­a­nism. First on the list of things to do is iden­tify what mol­e­cule binds at the allosteric site. "We don't know what the ligand is yet, but we think it's a mem­brane com­po­nent," said Mattos. This theory is sup­ported by the fact that RAS does most of its work when it's attached to a cell's inside wall.

If the researchers can under­stand this novel mech­a­nism for turning off RAS, they could pro­vide a new par­a­digm for cancer drug devel­op­ment. "Our group is proposing that we should be tar­geting these other sites close to the mem­brane," said Mattos. "If we inter­rupt this con­ver­sa­tion between RAS and the mem­brane inter­face, we're also going to be dis­rupting signaling."

Explore further: 3Qs: New clues to unlocking the genome

Related Stories

3Qs: New clues to unlocking the genome

September 19, 2012
Last week, Nature Mag­a­zine, Genome Research and Genome Biology pub­lished 30 papers on break­through research that will change the face of genetics. After nearly a decade of searching, the Ency­clo­pedia of DNA Ele­ments ...

The language of neural cells

August 23, 2012
Imagine if we could under­stand the lan­guage two neu­rons use to com­mu­ni­cate. We might learn some­thing about how thoughts and con­scious­ness are formed. At the very least, our improved under­standing of neuron ...

Validation for flu prediction

January 8, 2013
(Medical Xpress)—In 2009, the H1N1 virus slipped into the blood­streams of more than 40 mil­lion people around the world. In just four months, it killed more than 14,000 indi­vid­uals as it trav­eled from Mexico to ...

Recommended for you

Stem cell therapy attacks cancer by targeting unique tissue stiffness

July 26, 2017
A stem cell-based method created by University of California, Irvine scientists can selectively target and kill cancerous tissue while preventing some of the toxic side effects of chemotherapy by treating the disease in a ...

Understanding cell segregation mechanisms that help prevent cancer spread

July 26, 2017
Scientists have uncovered how cells are kept in the right place as the body develops, which may shed light on what causes invasive cancer cells to migrate.

Study uncovers potential 'silver bullet' for preventing and treating colon cancer

July 26, 2017
In preclinical experiments, researchers at VCU Massey Cancer Center have uncovered a new way in which colon cancer develops, as well as a potential "silver bullet" for preventing and treating it. The findings may extend to ...

Compound shows promise in treating melanoma

July 26, 2017
While past attempts to treat melanoma failed to meet expectations, an international team of researchers are hopeful that a compound they tested on both mice and on human cells in a petri dish takes a positive step toward ...

Study may explain failure of retinoic acid trials against breast cancer

July 25, 2017
Estrogen-positive breast cancers are often treated with anti-estrogen therapies. But about half of these cancers contain a subpopulation of cells marked by the protein cytokeratin 5 (CK5), which resists treatment—and breast ...

Breaking the genetic resistance of lung cancer and melanoma

July 25, 2017
Researchers from Monash University and the Memorial Sloan Kettering Cancer Center (MSKCC, New York) have discovered why some cancers – particularly lung cancer and melanoma – are able to quickly develop deadly resistance ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.