11 months ago

2004 Scientific Report

Our current research

Our current research focuses on molecular characterization of the MAPK pathway–associated survival signaling in melanoma cells. In particular, we are investigating the phosphorylation and inactivation of the pro-apoptotic protein Bad mediated by the 90-kDa ribosomal S6 kinase. Additionally, we are employing RNAi to evaluate the contribution of other Bcl-2 family members in the survival of melanoma cells. The molecular mechanism by which the inhibition of MAPK signaling specifically triggers apoptosis in human melanoma cells should reveal additional molecular targets useful for the prevention of and intervention in melanoma and other MAPK-associated cancers such pancreatic, lung, colon, and breast carcinomas, as well as gliomas. Additionally, further validation studies are ongoing to clinically develop the MAPK signaling pathway as a therapeutic target for melanoma treatment. Note: Work begun by Dr. Koo will be completed under the direction of George Vande Woude. Inquiries about the work should be directed to Dr. Vande Woude. External Collaborators Thomas M. Aaberg, Jr., Associated Retinal Consultants, Grand Rapids, Michigan Alan Campbell, Spectrum Health Cancer Program, Grand Rapids, Michigan Marianne K. Lang, Timothy J. O’Rourke, and Connie Szczepanek, Grand Rapids Clinical Oncology Program, Michigan Won Kyu Lee, Kent Pathology Laboratory, Ltd., Grand Rapids, Michigan Judith S. Sebolt-Leopold, Pfizer Global Research & Development, Ann Arbor, Michigan David J. Waters, Purdue University, West Lafayette, Indiana Lilly Research Laboratories, a division of Eli Lilly and Company, Indianapolis, Indiana Recent Publications Eisenmann, Kathryn M., Matthew W. VanBrocklin, Nancy A. Staffend, Susan M. Kitchen, and Han- Mo Koo. 2003. Mitogen-activated protein kinase pathway–dependent tumor-specific survival signaling in melanoma cells through inactivation of the proapototic protein Bad. Cancer Research 63(23): 8330–8337. Koo, Han-Mo, Nicholas S. Duesbery, and George F. Vande Woude. 2002. Anthrax toxins, mitogenactivated protein kinase pathway, and melanoma treatment. Directions in Science 1: 123–126. Koo, Han-Mo, Matt VanBrocklin, MaryJane McWilliams, Stephan H. Leppla, Nicholas S. Duesbery, and George F. Vande Woude. 2002. Apoptosis and melanogenesis in human melanoma cells induced by anthrax lethal factor inactivation of mitogen-activated protein kinase kinase. Proceedings of the National Academy of Sciences U.S.A. 99(5): 3052–3057. From left to right: Davidson, Kitchen, VanBrocklin 34

Laboratory of Integrin Signaling and Tumorigenesis Cindy K. Miranti, Ph.D. Dr. Miranti received her M.S. in microbiology from Colorado State University in 1982 and her Ph.D. in biochemistry from Harvard Medical School in 1995. She was a postdoctoral fellow in the laboratory of Joan Brugge at ARIAD Pharmaceuticals, Cambridge, Mass., from 1995 to 1997 and in the Department of Cell Biology at Harvard Medical School from 1997 to 2000. Dr. Miranti joined VARI as a Scientific Investigator in January 2000. She is also an Adjunct Assistant Professor in the Department of Physiology at Michigan State University. Laboratory Members Staff Suganthi Chinnaswamy, Ph.D. Mathew Edick, Ph.D. Robert Long, B.A. Veronique Schultz Patacsil, B.S. Students Beverly Illian Research Interests Our laboratory is interested in understanding the mechanisms by which integrin receptors, interacting with the extracellular matrix, regulate cell processes involved in the development of cancer. Using tissue culture models, biochemistry, molecular genetics, and mouse models, we are defining the cellular and molecular events involved in integrin-dependent adhesion and downstream signaling that are important for melanoma and prostate tumorigenesis and metastasis. Integrins are a class of heterodimeric transmembrane receptors that includes 15 alpha and 9 beta subunits. Each subunit contains a short cytoplasmic region that has no known enzymatic activity, but through protein-protein interactions it is able to interact with actin-containing microfilaments and specific signaling molecules. Consequently, the engagement of integrin receptors by extracellular matrix components induces actin microfilament rearrangement and activates many signal transduction pathways. Integrin and growth factor receptor cross-talk Our recent work has focused on characterizing the interactions between integrins and receptor tyrosine kinases. Adhesion of epithelial cells to several different extracellular matrices induces ligand-independent activation of the epidermal growth factor receptors EGFR and ErbB2 and of the HGF/SF receptor, Met. Overexpression of EGFR, ErbB2, or Met occurs in prostate cancer. We have demonstrated that by recruiting and activating EGFR, integrins stimulate a subset of integrin-induced signaling pathways (Fig. 1). In the absence of EGFR activation, the ability of the integrins to induce the Ras/Erk signaling pathway and the PI-3K/Akt pathway is severely impaired. However, not all integrin signaling pathways depend on EGFR; for instance, integrin-mediated activation of FAK, Src, or PKC is not dependent on EGFR. Future experiments will be aimed at determining how integrin activation of ErbB2 or Met contributes to integrin signaling. We have further demonstrated that integrinmediated adhesion of primary prostate epithelial cells is sufficient to induce several G1 cell cycle events, including increases in the levels of cyclin Figure 1. Integrin-induced activation of EGFR is required for a subset of integrin-regulated signaling pathways. EGFR is required for integrin activation of Cbl, PLCγ, Erk, and Akt. EGFR is not required for integrin activation of PKC, Src, or FAK. 35

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