Salk Institute for Biological Studies

Faculty

Reuben J. Shaw

Reuben J. Shaw

Professor
Molecular and Cell Biology Laboratory
Howard Hughes Medical Institute Early Career Scientist

Education

Research

Reuben Shaw, 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 metabolic disease.

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.

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Selected Publications

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