PTEN Tumor Suppressor Function, NF2 Protein, EPB50

Maria-Magdalena Georgescu, M.D., Ph.D.

A major focus of our laboratory is to elucidate the molecular mechanisms of cancer initiation and progression, specifically through the analysis of the PTEN tumor suppressor, a major tumor suppressor gene inactivated in cancers. As we unravel its structure, we investigate the biochemical pathways and molecular mechanisms responsible for PTEN's involvement in cancer cell proliferation and invasiveness. The regulation of PTEN's tumor suppressor function by its recruitment to macromolecular protein complexes is one of the major projects in my laboratory.

We are also investigating how the Neurofibromatosis 2 protein and related molecules from the same protein family (ERM ¡Xezrin, radixin, moesin) impact the pathogenesis and invasiveness of glioblastoma. We recently found that EBP50 (ERM-binding phophoprotein 50), an adaptor molecule that binds to NF2-ERM proteins, is necessary for their organization at the apical membrane of specialized polarized epithelial cells. EBP50 is mutated in human breast cancer and we are pursuing its role in brain tumors by using EBP50(-/-) mutant mice generated in the lab.

Overall, these projects involve techniques in protein biochemistry and cellular biology, and the analysis and generation of knock-out mice.

Selected Publications

Jiang Z, Pore N, Cerniglia GJ, Mick R, Georgescu MM, Bernhard EJ, Hahn SM, Gupta AK, Maity A. Phosphatase and tensin homologue deficiency in glioblastoma confers resistance to radiation and temozolomide that is reversed by the protease inhibitor nelfinavir. Cancer Res. 2007 May 1;67(9):4467-73.

Morales, F.C., Takahashi, Y., Momin, S., Adams, H., Chen, X., Georgescu, M.-M. NHERF1/EBP50 head-to-tail intramolecular interaction masks the association with PDZ-domain ligands. Mol. Cell. Biol. 27:2527-2537, 2007.

Kreimann, E.L., Morales, F.C., de Orbeta-Cruz, J., Takahashi, Y., Adams, H., Liu, T.-J., McCrea, P.D., Georgescu, M.-M. Cortical stabilization of ƒÒ-catenin contributes to NHERF1/EBP50 tumor suppressor function. Oncogene. 2007 Aug 9;26(36):5290-9.

Takahashi, Y., Morales, F., Kreimann, E., Georgescu, M.-M. PTEN tumor suppressor associates with NHERF proteins to attenuate PDGF receptor signaling. EMBO J. 25(4): 910-920, 2006.

Kissel H, Georgescu MM, Larisch S, Manova K, Hunnicutt GR, Steller H. The Sept4 septin locus is required for sperm terminal differentiation in mice. Dev Cell. 2005 Mar;8(3):353-64.

Wu Y, Singh S, Georgescu MM, Birge RB. A role for Mer tyrosine kinase in alphavbeta5 integrin-mediated phagocytosis of apoptotic cells. J Cell Sci. 2005 Feb 1;118(Pt 3):539-53.

Morales F, Takahashi Y, Kreimann E, Georgescu MM. Ezrin-radixin-moesin (ERM)-binding phosphoprotein 50 organizes ERM proteins at the apical membrane of polarized epithelia. Proc. Natl. Acad. Sci. USA 101:17705-17710, 2004.

Suzuki J, Sukezane T, Akagi T, Georgescu MM, Ohtani M, Inoue H, Jat PS, Goff SP, Hanafusa H, Shishido T. Loss of c-abl facilitates anchorage-independent growth of p53- and RB- deficient primary mouse embryonic fibroblasts. Oncogene. 2004 Nov 4;23(52):8527-34.

Sumitomo, M., Iwase, A., Navarro, D., Zheng, R., Kaminetzky, D., Shen, R., *Georgescu, M.-M., *Nanus, D. Synergy in tumor suppression by direct interaction of Neutral Endopeptidase with PTEN. Cancer Cell, 5:67-78, 2004. *equal contribution.

Radu A., Neubauer V., Akagi, T., Hanafusa, H., Georgescu, M.-M. PTEN induces cell-cycle arrest by decreasing the protein level and nuclear localization of cyclin D1. Mol. Cell. Biol., 23:6139-6149, 2003.