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

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: