Protein phosphorylation defines one of the most important and pervasive regulatory mechanisms in cell signaling. A precise control of the balance between phosphorylation and dephosphorylation is crucial for living organisms to maintain normal physiological functions. While protein kinases have been extensively studied in efforts of developing therapeutically relevant inhibitors, significant knowledge gaps exist on the opposing actions of protein phosphatases.

My laboratory has a long-standing interest in studying protein phosphatases and their relevance to cancer. Our research has been focused on determining the physiological role of a novel family of protein phosphatases, PHLPP, in regulating intestinal epithelial cell proliferation and apoptosis under normal and disease conditions. We were the first to show that PHLPP is frequently downregulated in colorectal cancer patients and that reintroduction of PHLPP into colon cancer cells inhibits cell proliferation in vitro and tumorigenesis in vivo. In addition, we identified PHLPP as a negative regulator of the RAS/RAF pathway that directly dephosphorylates RAF1 and inhibiting its kinase activity. Using knockout mouse models of PHLPP, we showed that PHLPP-loss promotes Apc-driven tumorigenesis in vivo by inhibiting apoptosis of intestinal epithelial cells. In addition, our studies have established PHLPP as an important regulator of glucose metabolism and ER stress in cancer cells. Recently, we have expanded our studies into other protein phosphatases. Our current work focuses on determining the mechanisms by which PTPRF, a receptor tyrosine phosphatase, regulates Wnt signaling.

Another area of research in my lab is to investigate mitochondria-dependent regulation of glucose and lipid metabolism in colon cancer. Using organoid models derived from normal and tumor tissues, we investigated the functional importance of mitochondria-dependent metabolism in regulating cancer cell signaling to maintain stem cell population in colon cancer. Furthermore, we are interested in studying how the metabolic interaction between adipocytes and cancer cells promotes cancer cell survival and stem cell functions.