From protein signaling to cancer drug development

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."

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