Primary Appointment

Dual/Joint/Adjunct Appointment

• Signal transduction

• Cancer metabolism

• Tumorigenesis and progression

Precise regulation of cellular signaling is important for cell growth and differentiation, cell metabolism, apoptosis, and organ and tissue development; dysregulation of cell signaling can lead to the development of cancer. Cancer develops as a result of alterations in normal intracellular and intercellular signaling. Protein kinases play important roles in transducing, amplifying, and integrating cellular signals and, thus, play a key role in the development of cancer. In my laboratory, we study tumorigenesis and tumor progression, focusing on the following research topics:

1. Understanding how cancer advances by altering cell metabolism. Tumorigenesis is often associated with altered carbohydrate metabolism, characterized by increased glucose uptake and elevated lactic acid production under aerobic conditions, which was first recognized by Otto Warburg 85 years ago. However, the exact molecular mechanisms underlying the altered glycolysis in cancer cells remain unclear. Notably, it was recently reported that tumor cells exclusively express pyruvate kinase isozyme type M2 (PKM2), which regulates the rate-limiting final step of glycolysis. Depletion of PKM2 in human cancer cells reverses the Warburg effect and inhibits tumor formation. We have elucidated that PKM2 has dual roles that are essential for tumorigenesis: regulating the Warburg effect and gene transcription for cell proliferation by binding to and transactivating Tyr-phosphorylated -catenin. The coordinated control of metabolism and proliferation by PKM2 is essential for tumor progression (Nature, 2011).
2. Understanding how cancer cells migrate, invade, and metastasize by altering cell–cell contract and cell–extracellular matrix (ECM) interaction and by facilitating intercellular crosstalk between tumor cells and neighboring cells. We have found that activation of growth factor receptor kinases, such as the epidermal growth factor receptor (EGFR), promotes tumorigenesis and tumor cell invasion and metastasis by disrupting cell–cell contact. This process is mediated by caveolae-dependent endocytosis of E-cadherin and snail-regulated transcriptional repression of E-cadherin (Cancer Cell, 4:499-515, 2003). In addition, EGFR activation initiates intracellular crosstalk between EGFR- and Wnt-induced signaling pathways and promotes beta-catenin transactivation by releasing beta-catenin from cell-adhesion complex. This regulation is accomplished by AKT-phosphorylated beta-catenin at S552, which facilities disruption of the E-cadherin–beta-catenin interaction, and ERK-CK2 protein kinase cascade-dependent phosphorylation of alpha-catenin at S641, which promotes abrogation of the interaction between beta-catenin and alpha-catenin (Molecular Cell, 36:547-59, 2009). Furthermore, the activation of EGFR or its downstream Ras will reduce focal adhesion by dephosphorylation and inhibition of the focal adhesion kinase (FAK), which is mediated by ERK-dependent FAK phosphorylation at S910. FAK phosphorylation at S910 results in PIN1-dependent prolyl isomerization of FAK and subsequent recruitment of PTP-PEST for FAK dephosphorylation at Y397 (Molecular Cell, 35:11-25, 2009). The combination of disrupted cell–cell contact, reduced focal adhesion, and accelerated turnover of focal contacts promotes tumor cell migration, invasion, and metastasis.
3. Understanding how cancer progresses by promoting cell survival. Cancer cells promote cell survival by upregulation of antiapoptotic molecules. In our research on the regulation of cell survival and apoptosis, we have found that c-Jun, a major transcription factor in the activating protein 1 (AP-1) family, is downregulated in response to stress stimulation and chemotherapeutic drug treatment. The downregulation of c-Jun, which is regulated by MEKK1 (functioning as a MAP kinase kinase kinase and an E3 ligase)-mediated ubiquitination (Molecular Cell, 9:945-956, 2002) and HDAC3-dependent transcriptional repression, promotes cell apoptosis (Molecular Cell, 25:219-232, 2007).
   

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Last updated: 12/6/2011