(Descripion edited, 2/25/2005) The long term goal of the proposed research is to understand the mechanisms by which ultraviolet (UV) irradiation from the sun damages human skin and causes premature skin aging and skin cancer. Premature skin aging occurs in all persons to varying degrees as a result of normal day-to-day outdoor activities. It is especially severe in persons with high levels of sun exposure due to occupation or lifestyle. Epidemiological studies worldwide have revealed a direct connection between the incidence of skin cancer and exposure to UV irradiation. Skin cancer is the most common type of cancer in the Caucasian population of the United States; with more than 500,000 to 1,000,000 cases diagnosed each year. The annual cost of treatment in the U.S. is estimated to be between $500 million and $1 billion. These findings are directly relevant to public health care in the largest sense, yet knowledge regarding the mechanisms by which solar UV irradiation damages skin is far from complete. Ultraviolet irradiation damages human skin by at least two interdependent, but distinct, mechanisms 1) DNA damage, which results in genetic mutations that lead to cellular transformation, and 2) activation of signal transduction pathways, which strongly induce matrix metalloproteinases, and other gene products, which promote a local tissue environment conductive to cancer formation. Emerging evidence indicates that tyrosine phosphorylation of the epidermal growth factor receptor (EGFR) is a primary driving force by which UV irradiation stimulates signal transduction pathways that induce matrix metalloproteinases. The focus of this proposal is to elucidate the molecular mechanisms by which UV irradiation increases EGFR tyrosine phosphorylation. The proposed studies will test the hypothesis that receptor-type protein tyrosine phosphatase-k (RPTP-k) specifically dephosphorylates EGFR. Reversible inhibition of RPTP-k by UV-generated oxidative stress results in increased EGFR tyrosine phosphorylation, which drives downstream signal transduction pathways.
Four Specific Aims are proposed: 1) Determine regulation of EGFR tyrosine phosphorylation and signaling by RPTP-k, 2) determine substrate specificity of RPTP-k, 3) determine functional domains of RPTP-k, and 4) determine the role of co-localization of EGFR and RPTP-k in caveolin-enriched membrane rafts in regulation of EGFR tyrosine phosphorylation and signaling. ? ?
