ANDREW P. LAUDANO Associate Professor Department of Molecular, Cellular and Biomedical Sciences Ph.D., University of California-San Diego, 1981 E-mail: alaudano@cisunix.unh.edu

A major emphasis of the research program is to understand how phosphory lation regulates proteins that can cause cancer. In some proteins loss of phosphory lation sites causes the proteins to be activated and converts normal cells into cancer cells. The mechanism by which phosphorylation prevents malignant transformation is unknown. Our lab has provided evidence that for one of these proteins (Src) the phosphorylated C-terminus acts as a negative regulator by binding to a region called the Src homology 2 domain (SH2) as shown in the figure. This finding may explain how several oncogenic viruses cause cancer. For example, in Rous sarcoma virus-infected chicken cells, the C-terminal phosphorylation site has been deleted. As a consequence, the Src protein cannot be regulated by binding its C terminus and causes tumors.

Current work indicates that phosphorylation of other oncogenic proteins and growth factor receptors may also regulate their activity by modulating intramolecular and intermolecular interactions. Antibodies targeted to specific regions of many oncogenic proteins have been generated. Some of these antibodies have the ability to distinguish between phosphorylated and nonphosphorylated forms of specific oncoproteins and growth factors and are being tested as clinical diagnostic reagents to detect active oncoproteins in tumor tissues.

REPRESENTATIVE PUBLICATIONS

Garcia, R., Bowman, T.L., Niu, G., Yu, H., Minton, S., Muro-Cacho, C.A., Cox, C.E., Falcone, R., Fairclough, R., Parsons, S., Laudano, A., Gazit, A., Levitzki, A., Kraker, A., Jove, R. Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells. Oncogene. 20(20):2499-513 (2001).

Turkson, J., Ryan, D., Kim, J.S., Zhang, Y., Chen, Z., Haura, E., Laudano, A., Sebti, S., Hamilton, A.D., and Jove, R. Phosphotyrosyl peptides block Stat3-mediated DNA binding activity, gene regulation, and cell transformation. J. Biol. Chem. 276(48): 45443-55 (2001).

Bagrodia, S., A.P. Laudano, and D. Shalloway. Accessibility of the c-src SH2 domain for binding is increased during mitosis. J. Biol. Chem. 269:10247-10251 (1994).

Liu, X., S.R. Brodeur, G. Gish, Z. Songyang, L.C. Cantley, A.P. Laudano, and T. Pawson. Regulation of c-Src kinase activity by the Src SH2 domain. Oncogene 8:1119-1126 (1993).

Bangalore, L., A.J. Tanner, A.P. Laudano, and D.F. Stern. Antiserum raised against a synthetic phosphotyrosine-containing peptide selectively recognizes p185neu/erc-2 and the epidermal growth factor receptor. Proc. Natl. Acad. Sci. USA 89:11637-11641 (1992).

McGrew, B.R., D.W. Nichols, V.P. Stanton, H. Cai, R. Whorf, V. Patel, G.M. Cooper, and A.P. Laudano. Phosphorylation occurs in the amino terminus of the raf-1 protein. Oncogene 7:33-42 (1992).