Loss of function mutations in STK11, encoding the Ser/Thr protein kinase, LKB1 are responsible for the familial hamartoma syndrome, Peutz Jeghers Syndrome (PJS). Importantly, recent studies have revealed sporatic mutations in STK11 in a variety of human cancers, including lung adenocarcinomas. LKB1 phosphorylates and activates AMP dependent protein kinase in response to energy stress, and thus plays a key role in energy homeostasis.
Funded by the National Cancer Institute, this project explores the hypothesis that the LKB1-AMPK signaling axis evolved to limit cell growth under conditions of energy stress, and that genetic or epigenetic aberrations, as well as transcriptional and post-transcriptional events that suppress LKBI function, allow tumor cells to override metabolic control mechanisms that normally limit cell growth under energy stress. The overall goal is to elucidate the signaling and metabolic network controlled by LKB1-AMPK and use this information to identify targets for therapeutic intervention in tumors that lack LKB1.