Reuben Shaw: A fated pathway

omeallyphoto.com

Reuben Shaw wanted nothing more than to study tumor suppressor genes, but his results took him on another path. "As fate has it," he sighs in mock defeat, "diabetes will be a part of my research from here on out."

In 1993 Shaw joined Tyler Jacks' laboratory at the Massachusetts Institute of Technology as a graduate student. Jacks' lab studied a number of tumor suppressors, including p53 and retinoblastoma. The latest to be cloned, neurofibromatosis type II (Nf2), held certain appeal. From its sequence, Nf2 looks like a cytoskeletal protein, not a molecule that would be related to cell growth. "It was a complete enigma," Shaw says. Shaw determined that the Nf2 gene's protein, called merlin, is part of the signaling pathway downstream of the GTPase Rac, which coincidentally he had studied as an undergrad. It was "one of the twists of scientific fate," he says.

Shaw had picked his next enigmatic target months before completing his PhD in 1999. As a postdoc with Lewis Cantley at Harvard Medical School, he went after the protein kinase LKB1, a little known tumor suppressor whose loss of function causes Peutz-Jeghers syndrome.

For three years Shaw investigated what LKB1 phosphorylated. When he finally identified the AMP-activated kinase (AMPK), ¹ it was too late: Dario Alessi and Grahame Hardie at the University of Dundee in Scotland beat him to the punch with an online publication. Shaw recalls, "It meant I was back to the drawing board to some extent, and the follow-up papers were going to have to be more interesting."

AMPK is a well-known metabolic regulator. Redoubling his efforts, Shaw linked AMPK to cancer ² and LKB1 to diabetes. He went on to show that the diabetes drug, metformin, works through this pathway. 3 In 2005 he started as an assistant professor at the Salk Institute to continue his studies on the commonalities between the diseases. Cantley, who in the 1990s made a related connection between the tumor suppressor PI3-kinase and metabolism, finds the links exciting.

"Here are two different cases of pathways that are playing major roles in glucose energy metabolism, and when they're out of control, cause cancer," says Cantley. It's important, he adds, not to neglect either disease but to study both, as Shaw has been doing. "I think that's where the future is, and there are not that many who have special insight into both diseases."