Dae Joon Kim
Assistant Professor of Pharmacology
Ph.D., Pennsylvania State University – University Park
protein tyrosine phosphatase, carcinogenesis, UVB irradiation, DNA damage repair, TC-PTP, Stat3, skin cancer
Tyrosine phosphorylation is an important mechanism that governs cellular responses to environmental toxins. The phosphorylation of proteins at tyrosine residues is catalyzed by protein tyrosine kinases (PTKs), and these events play critical roles in regulating cell proliferation, differentiation, and survival. Abnormalities affecting PTK-mediated phosphorylation are associated with various human diseases, including cancer.
Tyrosine phosphorylation by PTKs is balanced by dephosphorylation catalyzed by protein tyrosine phosphatases (PTPs), and these reciprocal response mechanisms regulate the rate and duration of the signaling pathways initiated and amplified by PTKs. There is increasing evidence suggesting that PTPs play central and specific roles in the regulation of signaling mechanisms, in addition to their housekeeping roles in the restoration of the dephosphorylated state for their target proteins. TC-PTP (TC45), one member of the PTP family, is known to dephosphorylate PTKs, such as Stat1, Stat3, and Stat5. These events are critical for maintenance of normal cell proliferation and cell cycle regulation. However, specific roles for TC-PTP in the context of disease states, especially in cancer and its molecular mechanisms, remain unexplored.
The primary focus of research in my laboratory is to identify roles played by TC-PTP in UVB-induced skin carcinogenesis. Our recent studies suggest that TC-PTP is centrally involved in the cutaneous response to UVB irradiation. In skin keratinocytes, TC45 is mainly localized in the cytoplasm, but it is translocated to the nucleus when the cells are subjected to UVB exposure. TC45 is responsible, in part, for the rapid dephosphorylation of Stat3 following UVB. We are currently working on four aspects of the roles played by TC-PTP in UVB-exposed skin cells, using both in vitro and in vivo approaches. These are: 1) the TC-PTP-mediated signaling mechanisms that control the UVB-induced DNA damage response in cultured mouse skin cells; 2) the mechanisms by which UVB induces cytoplasm-to nuclear translocation of TC45 in these cells; 3) the signaling pathways by which TC-PTP contributes to carcinogenesis in these cells; and 4) the role played by TC-PTP in UVB- induced carcinogenesis in intact skin of living animals.
We expect that our work will identify specific functional roles of PTPs in the molecular and cellular mechanisms of environmentally-induced skin carcinogenesis. By doing this, our studies will also identify novel therapeutic targets for the prevention and treatment of skin cancers and, perhaps, for other tumor types as well.