Reuben J. Shaw
B.S. Biology, Cornell University, Ithaca, NY
Ph.D., Biology, Massachusetts Institute of Technology, Cambridge, MA
Postdoctoral Fellow, Harvard Medical School, Boston, MA
Reuben Shaw, associate professor in the Molecular and Cell Biology Laboratory and the Dulbecco Laboratory for Cancer Research, studies signal transduction pathways that underlie the development of cancer as well as type 2 diabetes.
Our work centers around a human tumor suppressor named LKB1. LKB1 is mutationally inactivated in the familial cancer disease Peutz-Jegher Syndrome as well as in a large percentage of sporadic lung adenocarcinomas. 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 well known highly conserved regulator of cell metabolism that is activated under conditions of energy stress. 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 cellular 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.
One way that LKB1 and AMPK regulate tumorigenesis is through regulation of the mTOR kinase, a conserved integrator of nutrient and growth factor signaling. We found that AMPK directly phosphorylates the TSC2 tumor suppressor and activates it to inhibit mTOR signaling. Consistent with this observation from cell culture, tumors lacking LKB1 were found to contain elevated levels of mTOR compared to surrounding epithelium. These findings culminated in the observation that three different human hamartoma syndromes, involving loss of TSC1/2, PTEN, and LKB1, all share a common biochemical underpinning: hyperactivation of mTOR signaling. We also generated a tissue-specific knockout of LKB1 in liver and also observed dramatic elevations of mTOR signaling in this context.
We chose to knockout LKB1 in liver as liver is known to be a tissue where AMPK activity is thought to be critical. Indeed, we found that loss of LKB1 led to a complete loss of AMPK activation and severe diabetes-like phenotypes in in these mice. We found that both gluconeogenic and lipogenic gene expression were upregulated in the livers of these mice, due in part to the loss of phosphorylation of a critical transcriptional coactivator termed TORC2 by AMPK and related kinases in the absence of LKB1. Finally we showed that metformin, one of the most widely prescribed type 2 diabetes therapeutics in the world, requires LKB1/AMPK signaling in the liver in order to exert its therapeutic benefit.
Future studies in our lab will focus on further elucidating these critical signaling pathways at this emerging interface between cancer and diabetes. We will employ a variety of biochemical, cell-biological, and genetic mouse models to dissect these biological processes. In addition, we will examine how existing diabetic therapeutics may be useful in the treatment of tumors with defined genetic lesions.
"We investigate the mechanisms connecting cell metabolism to
growth control by studying an ancient signaling pathway that
goes awry in both cancer and type 2 diabetes. By understanding
the connection between these diseases, we pave the way to
better therapies for both."
While investigating one of the most commonly
mutated genes in lung cancer, LKB1,
Shaw's lab discovered that the gene directly
activates a metabolic master switch known
as AMPK. This direct connection of LKB1
to AMPK provided a stronger molecular link
between cancer and diabetes than was ever
known previously. The lab went on to molecularly
decode a number of new components
of this biochemical pathway that connects
nutrition to both cancer and diabetes. In the
past two years, their studies have led to the
discovery of new therapies for both cancer
and type 2 diabetes.
Recently, Shaw's group found that AMPK
initiates a cellular recycling process known
as autophagy, which allows cells to dispose
of toxins, by activating an enzyme known
as ULK1. To test the effects on autophagy
of deregulating these enzymes, the group focused
on large intracellular structures called
mitochondria, whose role is to generate energy.
Mitochondria are easily damaged in
detoxifying tissues like liver, and defective
mitochondria are turned over through a special
form of autophagy called mitophagy. The
researchers found that the ability to recycle
their defective mitochondria allowed cells to
survive starvation better. This work suggests
that drugs regulating ULK1 itself may be
useful for treating certain forms of cancer or
The Shaw lab also discovered another new
set of AMPK targets, but in this case focused
on targets that may be key for diabetes,
knowing that AMPK is one of the critical
enzymes controlled by the widely used diabetes
drug metformin. They discovered that
proteins known as histone deacetylases
(HDACs) are regulated by AMPK and play a
vital role in directing glucose production in
the liver. Normally, in response to fasting,
hormonal cues tell the liver to produce its
own glucose from scratch to keep the body
alive, and these HDACs are required in liver
cells for the hormone to transmit that signal.
This new finding—that HDACs play a critical
role in diabetes—further connects metabolic
disease with cancer. Prior to this, a number
of HDAC inhibitor drugs were being evaluated
in clinical trials as potential treatments
for cancer, some of which now may find
utility in the treatment of diabetes.
Awards and Honors
- Howard Hughes Medical Institute Early Career Scientist Award (2009-2015)
- Hearst Assistant Professorship Chair (2009-2012)
- American Diabetes Association Junior Faculty Award (2008-2011)
- American Cancer Society Research Scholar (2007-2011)
- V Scholar for Cancer Research (2006-2007)
Mihaylova, M.M. and Shaw, R.J. (2013) Metabolic reprogramming by class I and II histone deacetylases. Trends Endocrinol Metab 24:48-57.
Shackelford, D.B., Abt, E., Gerken, L., Vasquez, D.S., Atsuko, S., Leblanc, M., Wei, L., Fishbein, M.C., Czernin, J., Mischel, P.S. and Shaw, R.J. (2013) LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin. Cancer Cell 23:143-158.
Auricchio, N., Malinowska, I., Shaw, R., Manning, B.D., and Kwiatkowski, D.J. (2012). Therapeutic trial of metformin and bortezomib in a mouse model of tuberous sclerosis complex (TSC). PLoS ONE 7:e31900.
Shaw, R.J. and Cantley, L.C. (2012) Decoding key nodes in the metabolism of cancer cells: sugar & spice and all things nice. F1000 Biol Rep 4:2.
Shaw, R.J. and Cantley, L.C. (2012) Ancient Sensor for Ancient Drug. Science 336:813-4.
Svensson, R.U. and Shaw, R.J. (2012) Cancer metabolism: Tumour friend or foe. Nature 485:590-591.
Xia, Y., Yeddula, N., LeBlanc, M., Ke, E., Zhang, Y., Oldfield, E., Shaw, R.J. and Verma, I.M. (2012) Reduced cell proliferation by IKK2 depletion in a mouse lung-cancer model. Nat Cell Biol 14:257-65.
Akhtar, A., Fuchs, E., Mitchison, T., Shaw, R.J., St. Johnston, D., Strasser, A., Taylor, S., Walczak, C. and Zerial, M. (2011) A decade of molecular cell biology: achievements and challenges. Nat Rev Mol Cell Biol 12:669-674.
Mihaylova, M.M., Vasquez, D.S., Ravnskjaer, K., Denechaud, P-D., Yu, R.T., Alvarez, J.G., Downes, M., Evans, R.M., Montminy, M. and Shaw, R.J. (2011) Class IIa Histone Deacetylases are Hormone-activated regulators of FOXO and Mammalian Glucose Homeostasis. Cell 145, 1-15. [doi:10.1016/j.cell.2011.03.043]
Li, Y., Xu, S., Mihaylova, M., Zheng, B., Hou, X., Jiang, B., Park, O., Luo, Z., Lefai, E., Shyy, J.Y-J., Gao, B., Wierzbicki, M., Verbeuren, T.J., Shaw, R.J., Cohen, R.A. and Zang, M. (2011) AMPK Phosphorylates and Inhibits SREBP Activity to Attenuate Hepatic Steatosis and Atherosclerosis in Diet-induced Insulin Resistant Mice. Cell Metab 13, 376-388.
Mair, W., Morantte, I., Rodrigues, A.P., Manning, G., Montminy, M., Shaw, R.J. and Dillin, A. (2011) Lifespan extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB. Nature 470, 404-408.
Egan, D.F., Shackelford, D.B., Mihaylova, M.M., Gelino, S.R., Kohnz, R.A., Mair, W., Vasquez, D.S., Joshi, A., Gwinn, D.M., Taylor, R., Asara, J.M., Fitzpatrick, J., Dillin, A., Viollet, B., Kundu. M., Hansen, M. and Shaw, R.J. (2011) Phosphorylation of ULK1 (hATG1) by AMP-Activated Protein Kinase Connects Energy Sensing to Mitophagy. Science 331, 456-461.
Shackelford, D.B. and Shaw, R.J. (2009) The LKB1-AMPK pathway: metabolism and growth control in tumor suppression. Nat. Rev. Cancer, 9, 563-575.
Shackelford, D.B., Vasquez, D.S., Corbeil, J., Wu, S., Leblanc, M., Wu, C.L., Vera, D.R., and Shaw, R.J. (2009) mTOR- and HIF-1a mediated tumor metabolism in an LKB1 mouse model of Peutz-Jeghers syndrome. PNAS 106, 11137-11142.
Narkar, V.A., Downes, M., Yu, R.T., Wang, Y.X., Kanakubo, E., Banayo, E., Mihaylova, M.M., Nelson, M.C., Zou, Y., Juguilon, H., Kang. H., Shaw, R.J., and Evans. R.M. (2008) AMPK and PPARβ/δ agonists are exercise mimetics. Cell 134, 405-415.
Gwinn, D.M., Shackelford, D.B., Egan., D.F., Mihaylova, M.M., Mery, A., Vasquez, D.S., Turk, B.E., and Shaw, R.J. (2008) AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 30, 214-26.
Shaw, R.J. Glucose metabolism and cancer (2006) Curr. Opin. Cell Biol. 18, 598-608.
Shaw, R.J. and Cantley, L.C. (2006) Ras, PI3(K), and mTOR signaling control tumor cell growth. Nature 441, 424-430.
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
Salk News Releases
- Diabetes drug could hold promise for lung cancer patients, January 29, 2013
- Salk Institute announces faculty promotions, April 2, 2012
- Salk researchers find new drug target for lung cancer, February 15, 2012
- "Fasting pathway" points the way to new class of diabetes drugs, May 12, 2011
- Hungering for longevity—Salk scientists identify the confluence of aging signals, February 17, 2011
- How cells running on empty trigger fuel recycling, December 23, 2010
- Hungry cells: Tumor metabolism discovery opens new detection and treatment possibilities for rare form of colon cancer, June 15, 2009
- Salk Launches Center for Nutritional Genomics with $5.5 Million Grant from Helmsley Trust, April 22, 2009
- Salk scientist -- one of 50 nationwide -- selected as HHMI Early Career Scientist, March 26, 2009
- AMPK signaling: Got food?, April 24, 2008
- Salk Institute's new faculty scientist conducts basic research on molecular pathways at intersection of diabetes and cancer, January 10, 2006
© Salk Institute for Biological Studies
10010 North Torrey Pines Road, La Jolla, CA 92037 | 858.453.4100