Public Release: 

AMPK signaling: Got food?

Salk Institute


IMAGE: In response to energy stress, AMPK, which acts like a gas gauge by sensing how much energy a cell has, puts a damper on cell proliferation. It muffles a cellular... view more


A team of scientists at the Salk Institute for Biological Studies think they know how many--if not most--living organisms answer this question. They recently showed that when food supplies dwindle, mammals, fruitflies, or frogs probably activate the same ancient cell signaling pathway in order to conserve energy.



"This paper provides the first direct biochemical explanation for how cell growth is inhibited under conditions when nutrients are low," reports Shaw. "This very simple bio-circuit is literally the bare bones signal that most organisms use to say, 'We've got food!' "

Researchers knew that when this circuit broke down, cells facing starvation simply continued to divide--oblivious to hard times and spending energy currency like a frenzied credit card shopper--until the cellular cash ran out and cells died. What Shaw wondered was whether all the circuit components had been identified.



That's where Shaw's latest investigations began. "We were trying to understand how mutation of the tumor suppressor LKB1 leads to colon cancer or sporadic lung cancer," he says. "I had shown that LKB1 turns AMPK on, so the next question was, what does that do" If it regulated cancer, there had to be components of the pathway that regulated cell growth that no one had discovered."

A collaborator, Benjamin Turk, Ph.D., of Yale University School of Medicine, helped Shaw identify that component. AMPK is a kinase, meaning that it adds phosphate groups--which sometimes activate and other times inhibit--to target proteins. Using Turk's data, Shaw combed through collections of protein fragments biochemically phosphorylated by AMPK and fished out one corresponding to a novel candidate--raptor. Remarkably that tiny part of raptor protein looked similar in raptor proteins expressed in organisms ranging from slime molds to humans.


The study provides stunning insight into Mother Nature's reluctance to tinker with strategies that meet organisms' most basic needs. "Simply the most rudimentary information that any cell needs is to know whether there is food around--that's what AMPK senses. If there is not, you need to turn off factors that make cells grow," explains Shaw, specifically to the growth-promoting team of raptor and mTOR.

And as if solving evolutionary puzzles and dissecting tumor suppressor pathways isn't enough, Shaw's work overall hints at an even more profound clinical association: the widely used type 2 diabetes drug metformin activates AMPK, suggesting that the LKB1/AMPK pathway is a molecular link between diabetes and cancer. "This circuit could in part explain the increased cancer risk seen in type 2 diabetic patients," says Shaw, noting many are predisposed to breast, prostate or colon cancer.


Those questions are next on Shaw's agenda. "Not only will we continue to dissect this pathway biochemically, but we will more directly test whether we can treat certain types of tumors in mouse models with diabetes drugs," Shaw says.



