Oncogenes and Signal Transduction in Tumor Formation and Suppression
Zhimin Lu, M.D., Ph.D.
Precise regulation of cellular signaling is important for cell growth and differentiation, 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:
- 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, 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.
- 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).
- Understanding how cancer advances by altering cancer 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 75 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 are seeking to elucidate the mechanisms of altered cancer cell metabolism driven by regulation of PKM2.
Ji H, Wang J, Hawke D, Keezer S, Ge Q, Fang X, Litchfield D, Aldape K, Lu Z. EGF-induced ERK activation promotes CK2-mediated dissociation of -catenin from -catenin and transactivation of -catenin. Mol Cell, in press.
Lu Z, Hunter T. Degradation of activated protein kinases by ubiquitination. Ann Rev Biochem. 78:435–75, 2009.
- Zheng Y, Xia Y, Hawke D, Halle M, Tremblay M, Gao X, Zhou X, Aldape K, Cobb M, Xie K, He J, Lu Z. FAK Phosphorylation by ERK Primes Ras-Induced Tyrosine Dephosphorylation of FAK Mediated by PIN1 and PTP-PEST. Mol Cell 35:11–25, 2009 (Highlighted in Mol Cell and Faculty of 1000 Biology).
Xia Y, Wang J, Liu TJ, Yung WK, Hunter T, Lu Z. c-Jun downregulation by HDAC3-dependent transcriptional repression promotes osmotic stress-induced cell apoptosis. (Selected as the feature article by Mol Cell, Highlighted in Faculty of 1000 Biology, and received MD Anderson Nycomed GmbH Outstanding Research Publication Award in 2007). Mol Cell 25:219-32, 2007.
Lu Z*, Ghosh S, Wang Z, Hunter T*. (*Corresponding authors) Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of beta-catenin, and enhanced tumor cell invasion. Cancer Cell 4(6):499-515, 12/2003. (Highlighted in Nat Rev Cancer 2004; 4:90-91; Nature Signaling & Update/ The signaling gateway 2004, and Faculty of 1000 Biology).
Lu Z, Xu S, Joazeiro C, Cobb MH, Hunter T. The PHD domain of MEKK1 acts as an E3 ubiquitin ligase and mediates ubiquitination and degradation of ERK1/2. Mol Cell 9(5):945-56, 5/2002. (Highlighted in Nat Rev Mol Cell Biol 2002;3:473; Nature-Signaling Update/ the signaling gateway, 2002; and Faculty of 1000 Biology).