Research Interests

Almost all cellular programs are regulated by phosphorylation, of which an important aspect is the controlling of cell proliferation, survival and apoptosis. Dysregulation of responsible kinases has often been found to contribute to the unrestrained growth of cancer cells. Thus, the overall research interest of my laboratory is to understand how protein phosphorylation regulates cell function, and how its alteration causes diseases such as cancer and metabolic disorders. In addition, we are interested in developing new approaches for their treatment and prevention. Our current research focuses on the regulation and function of Raf kinase and AMP-activated protein kinase, both of which have been implicated in cancer and other disorders, when they are dysregulated or their genes are mutated.

1. The Raf kinase family, consisting of three isoforms, Raf-1, B-Raf and A-Raf, serves as an immediate downstream effector of Ras (See diagram 1). Raf kinase is a prototypical MEK Kinase that directly phosphorylates and activates MEK in response to extracellular stimuli. It is also implicated in tumorigenesis, inasmuch as activating mutations of the ras genes have been found in 20-30% of human cancers and activated mutants of B-Raf often reported in human cancers as well. Although the linear relationship of the Ras/Raf/MEK/Erk signaling pathway has been delineated, the mechanism of Raf activation still remains elusive. We have a long standing interest in characterizing phosphorylation of Raf for its activation, and identifying kinases responsible for these phosphorylation events and downstream targets in addition to MEK1/2. Using immunoprecipitation and mass spectrometry, we have identified several new kinases associated with Raf and are currently determining if they function downstream or upstream of Raf.

Diagram 1. Raf kinase signaling.

2. AMPK is a fuel-sensing enzyme that is activated when cells are deprived of nutrients (energy crisis), and inhibited when they are surfeited with nutrients. Recent studies have suggested a link between AMPK and cancer. For example, (1) a number of molecules including mTOR, fatty acid synthase (FAS) and acetyl CoA carboxylase (ACC), which are necessary for the growth of many types of human cancer cells, are inhibited by AMPK and; (2) AMPK has been identified as a physiological substrate for the tumor suppressor LKB1, a serine/threonine protein kinase, and as an upstream activating kinase for another tumor suppressor, tuberous sclerosis complex 2 (TSC2). We have shown that sustained activation of AMPK by pharmacological activators attenuates the growth of cancer cells, concomitant with the inhibition of mTOR and FAS and upregulation of p21. In light of these findings, we hypothesize that AMPK may function as a metabolic tumor suppressor (see diagram 2). In energy surplus, AMPK restrains biosynthetic processes in order to control cell growth; in contrast, when cells are deprived of energy, AMPK inhibits the ATP-consuming anabolic processes that are not required for acute cell survival, and stimulates fatty acid oxidation to generate more ATP to cope with stress. As a result, energy is preserved for acute cell survival programs. Although loss-of-function mutations have not been documented in cancer yet, it is possible that metabolic alterations in cancer cells could lead to dysregulation of AMPK. Thus, we are currently examining whether AMPK activity is suppressed in cancer cells and if so, whether it is associated with altered metabolic states such as increased glycolysis and de novo fatty acid synthesis. We are also evaluating functional relationship between AMPK and other tumor suppressors and oncogenes in the regulation of cancer cell growth. Finally, we will assess the effects of AMPK activators and inhibitors on tumor development using animal models, and identify new partners for AMPK in regulating the growth of cancer cells.

Diagram 2. Interaction of AMPK with tumor suppressors and oncogenes.