- PROFESSOR Microbiology
- PROFESSOR Oncological Sciences
Ph.D., University of California Berkeley
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Mechanism of cell transformation and oncogenicity of receptor protein tyrosine kinases
The primary interest of this laboratory is to study the normal signaling and oncogenic functions of receptor protein tyrosine kinases (RPTKs) and their down stream mediators to identify the basis for cell transformation and oncogenesis. It is also the interest of my laboratory to identify specific molecular targets for the development of anti-cancer therapeutics. Currently, we are studying the human insulin receptor (IR), human insulin-like growth factor I receptor (IGF-1R) and ros oncogene, which was originally discovered in an avian sarcoma virus by us. In addition to those RPTks, we are also examining the functional role of Vav3, a GTPase exchange factor, RACK1, a WD motif-containing protein and MOST, a newly discovered STAT3 modulator, in cell growth, apoptosis and transformation. Signal transduction pathways responsible for distinct transforming functions of those receptor PTKs and the above mentioned molecules are being explored. Regulation and intervention of those oncogenic RPTKs and signaling molecules by potential suppressors such as dominant-negative mutants or siRNA are being inquired. Molecular basis for epithelial mesenchyme transition and invasion is being investigated. Potential role of various RPTKs and their downstream signaling molecules in the development and progression of human malignancy, particularly breast and ovarian cancer, are being examined by cell culture system and animal models.
Using normal and oncogenic Ros, IR and IGF-1 receptor PTKs, a series of variants have been molecularly engineered and they display a wide spectrum of cell transforming ability and oncogenicity. Likewise, mutants of Vav3, RACK1 and MOST have also been engineered. These molecular reagents are used to explore the basis for distinct cell transforming properties such as morphological alteration, escape of contact inhibition, anchorage independent growth, resistance to apoptosis and enhanced migration and invasion. The wild-type (oncogenic) and the loss of function mutants are compared for their signal transduction pathways and functions to identify important molecules mediating various transforming properties. Constitutively activated and dominant negative mutants, as well as RNAi or siRNA vectors of signaling molecules are constructed and used to assess their effect on normal and transforming function of those RPTKs and the down stream signaling molecules. Potential novel substrates of the RPTKs have been investigated using the yeast two hybrid screening assay. Novel signaling molecules identified this way include STAT5 and MOST for IR and IGF-1 receptors, RACK1 for IGF-1 receptor and Vav3 for Ros, insulin, IGF-1 and EGF receptors. To study the kinetics of the signal transducing processes of those RPTKs, temperature sensitive mutants and ligand responsive chimeric receptors have been constructed for dissecting the processes.
Finally, the role of those RPTKs and their downstream signaling components in the growth and oncogenicity of human breast and ovarian cancer cells are explored with a series of breast and ovarian cancer cell lines and tumor tissues. Possible over-expression of certain RPTKs and related mediators including Twist and AKT in the tumorigenicity are being assessed using various molecular agents as described above.
Zhang W, Cheng GZ, Hermanto U, Zong CS, Chan J, Cheng J, Wang L. RACK1 and CIS mediate the degradation of BimEL in cancer cells. JBC 2008; 283: 16416-16426.
Wang L. Overview of modular domains and adaptor proteins pp1-32. In: Georges M, editor. Adaptor proteins and cancer. Kerala, India, Transworld Research Network, Trivandrum-695 023; 2008.
Cheng GZ, Zhang W, Sun M, Wang Q, Coppola D, Costanzo C, Xu LM, Chan J, Cheng JQ, Wang L. Twist is Induced by Activation of STAT3 and Mediates STAT3 Oncogenic Function. JBC 2008; 283: 14665-14673.
Uttamsingh S, Bao X, Nguyen KT, Bhanot M, Chan J, Liu F, Chu T, Wang L. Synergistic effect between EGF and TGF-1 in inducing oncogenic properties of intestinal epithelial cells. Oncogene 2008; 27: 2626-2634.
Cheng GZ, Zhang W, Wang L. Regulation of cancer cell survival, migration and invasion by Twist: AKT2 comes to interplay. Cancer Research 2008; 68: 957-960.
Cheng GZ, Chan J, Sun CD, Wang Q, Zhang W, Wang L. Twist transcriptionally upregulates AKT2 in invasive breast cancer cells leading to increased migration and survival. Cancer Research 2007; 67: 1979-1987.
Wang L, Chan J, Li W, . Rapamycin together with herceptin significantly increased anti-tumor efficacy compared to either alone in ErbB2 over expressing breast cancer cells. Intl. J. Cancer 2007; 121: 2911-2918.
Zhang W, Zong CS, Hermanto U, Lopez-Bergami P, Ronai Z, Wang L. RACK1 recruits STAT3 specifically to insulin and IGF-1 receptors for activation, which is important for regulating anchorage independent growth. Mol Cell Biol 2006; 26: 413-24.
Lopez-Bergami P, Hasen H, Bhoumik A, Zhang W, Wang L, Ronai Z. Receptor for RACK1 mediates activation of JNK by protein kinase C. Mol. 19; 2005: 309-320.
Wang L. Molecular signaling regulating anchorage-independent growth of cancer cells. The Mount Sinai J. of Medicine 2004; 71: 361-7.
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Dr. Wang has not yet completed reporting of Industry relationships.
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