(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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES012920-01A2
Application #
6988031
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Humble, Michael C
Project Start
2005-07-01
Project End
2010-05-31
Budget Start
2005-07-01
Budget End
2006-05-31
Support Year
1
Fiscal Year
2005
Total Cost
$327,038
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Dermatology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Xu, Yiru; Xue, Siliang; Zhou, Jin et al. (2015) Notch and TGF-? pathways cooperatively regulate receptor protein tyrosine phosphatase-? (PTPRK) gene expression in human primary keratinocytes. Mol Biol Cell 26:1199-206
Xu, Yiru; Fisher, Gary J (2013) Role of met axis in head and neck cancer. Cancers (Basel) 5:1601-18
Xu, Yiru; Zhou, Jin; Carey, Thomas E et al. (2012) Receptor-type Protein tyrosine phosphatase ? regulates met phosphorylation and function in head and neck squamous cell carcinoma. Neoplasia 14:1015-22
Xu, Yiru; Fisher, Gary J (2012) Receptor type protein tyrosine phosphatases (RPTPs) - roles in signal transduction and human disease. J Cell Commun Signal 6:125-38
Xu, Yiru; Xia, Wei; Baker, Dustin et al. (2011) Receptor-type protein tyrosine phosphatase beta (RPTP-beta) directly dephosphorylates and regulates hepatocyte growth factor receptor (HGFR/Met) function. J Biol Chem 286:15980-8
Xu, Yiru; Baker, Dustin; Quan, TaiHao et al. (2010) Receptor type protein tyrosine phosphatase-kappa mediates cross-talk between transforming growth factor-beta and epidermal growth factor receptor signaling pathways in human keratinocytes. Mol Biol Cell 21:29-35
Xu, Yiru; Shao, Yuan; Zhou, Jin et al. (2009) Ultraviolet irradiation-induces epidermal growth factor receptor (EGFR) nuclear translocation in human keratinocytes. J Cell Biochem 107:873-80
Xu, Yiru; Shao, Yuan; Voorhees, John J et al. (2006) Oxidative inhibition of receptor-type protein-tyrosine phosphatase kappa by ultraviolet irradiation activates epidermal growth factor receptor in human keratinocytes. J Biol Chem 281:27389-97
Xu, Yiru; Voorhees, John J; Fisher, Gary J (2006) Epidermal growth factor receptor is a critical mediator of ultraviolet B irradiation-induced signal transduction in immortalized human keratinocyte HaCaT cells. Am J Pathol 169:823-30