Reuben Shaw
 Assistant Professor, The Salk Institute

e-mail: shaw@salk.edu
Lab Homepage: Shaw Lab

     We are studying a highly conserved signal transduction pathway that controls both tumorigenesis and diabetes. We use a combination of biochemical, cell-biological, and genetic mouse models to dissect these disease states.

     Our work centers around a human tumor suppressor named LKB1. LKB1 is mutationally inactivated in the familial cancer disease Peutz-Jeghers Syndrome as well as in large percentage of sporadic lung adenocarcinomas (a common smoking-induced tumor). Interestingly, LKB1 encodes a threonine kinase that serves to activate a number of downstream kinases, including the AMP-activated protein kinase (AMPK), which is a critical regulator of metabolism, and the par-1/MARK family of kinases that regulate cell polarity.

     Using a combination of proteomic and bioinformatics approaches, we identified AMPK as a direct substrate of LKB1. AMPK is a highly conserved regulator of cell metabolism that is activated under conditions of energy stress, - (such as low glucose or hypoxia). nutrients and AMPK is also activated in critical metabolic tissues such as liver and muscle following exercise or in response to adipokines such as leptin and adiponectin.-. We propose that the LKB1-dependent activation of AMPK in response to these stress stimuli may act as a low energy checkpoint in the cell. This unexpected connection between a well-known regulator of metabolism and a tumor suppressor gene led to two immediate questions: Does AMPK have a role in tumor suppression and conversely, does the LKB1 tumor suppressor have a role in metabolic control in critical tissues in mammals? We have found that indeed both are true and that through the phosphorylation of specific targets by AMPK, these wide effects on physiology are regulated.

     We are currently further identifying critical new components of this tumor suppressor pathway and defining new substrates of AMPK and its related family members that play a role in controlling cell polarity, cell growth, cell senescence, and longevity.

     In addition, we are more broadly examining the question of how deregulation of metabolism may contribute to cancer. One of the very first properties found to be unique to tumor cells as opposed to their normal counterparts was- increased rates of glycolysis, a phenomena referred to as the Warburg effect, for Otto Warburg who won the Nobel Prize in 1931. Today we know much more about the signaling pathways that stimulate increased glycolysis in cancer cells, including the PI3-kinase, mTOR, and HIF-pathways. However, it remains unclear whether this metabolic deregulation is causally required for tumorigenesis. We are particularly interested in whether modulation of AMPK during tumor development contributes to, or is merely affected by, this energy switch. Finally, human metabolic disorders such as diabetes and obesity are associated with increased risk for certain forms of cancer. We are examining this issue in genetic mouse models aimed at dissecting whether how increased blood glucose and lipid contribute to increased mitogenic signaling in certain epithelial lineages.

    Shaw, R.J. (2006). Cell metabolism and cancer. Curr Opin Cell Biol, (in press)

    Shaw, R.J. and Cantley, L.C. (2006). Ras, PI3K, and mTOR: obligate signaling pathways for cancer. Nature, (in press)

    Shaw, R.J., Lamia, K.A., Vasquez, D., Koo, S.H., Bardeesy, N., DePinho, R.A., Montminy, M., Cantley, L.C. (2005). The Kinase LKB1 Mediates Glucose Homeostasis in Liver and Therapeutic Effects of Metformin. Science 310: 1642-6.

    Shaw, R.J., Bardeesy, N., Manning, B., Lopez, L. Kosmatka, M., DePinho, R.A., and Cantley, L.C. (2004). The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6: 91-99

    Shaw, R.J., Kosmatka, M., Bardeesy, N., Hurley, R.L., Witters, L.A., DePinho, R.A., Cantley, L.C. (2004). The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. PNAS 101: 3329-3335.

Reuben Shaw received his Ph.D. from M.I.T in the Center for Cancer Research. He then completed postdoctoral studies in the Department of Systems Biology at Harvard Medical School.