Receptor Protein Tyrosine Phosphatase-k Regulation of EGFR

受体蛋白酪氨酸磷酸酶-k 对 EGFR 的调节

• 批准号: 7626734
• 负责人: GARY J FISHER
• 金额: $ 30.19万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7626734
• 关键词: Caucasians; Caucasoid Race; Caveolae; Caveolins; DNA Damage; Data; Diagnosis; Distal; Docking; Dominant-Negative Mutation; Environment; Epidemiologic Studies; Epidermal Growth Factor Receptor; Exposure to; Fibronectins; Gene Mutation; Genes; Goals; Healthcare; Human; Incidence; Knowledge; Lead; Life Style; Ligands; Malignant Neoplasms; Matrix Metalloproteinases; Mediating; Membrane; Molecular; Occupations; Oxidation-Reduction; Oxidative Stress; Persons; Phosphorylation; Phosphotyrosine; Population; Protein Tyrosine Phosphatase; Proteins; Proto-Oncogene Protein c-met; Public Health; Receptor Activation; Receptor Inhibition; Receptor Protein-Tyrosine Kinases; Regulation; Relative (related person); Research; Research Personnel; Role; Signal Transduction; Signal Transduction Pathway; Skin; Skin Aging; Skin Cancer; Small Interfering RNA; Specificity; Substrate Specificity; Sun Exposure; Surface; Technology; Testing; The Sun; Tissues; Treatment Cost; Tyrosine; Tyrosine Phosphorylation; UV induced; United States; base; cancer type; driving force; extracellular; formycin triphosphate; human PTPRT protein; in vivo; keratinocyte; keratinocyte growth factor receptor; man; metaplastic cell transformation; novel; premature; programs; receptor; response; ultraviolet; ultraviolet irradiation

DESCRIPTION (provided by applicant): (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.

描述（由申请人提供）：（描述编辑，2005年2月25日）拟议研究的长期目标是了解来自太阳的紫外线（UV）照射损害人类皮肤并导致皮肤过早老化和皮肤癌的机制。由于正常的日常户外活动，所有人都会不同程度地发生皮肤过早老化。由于职业或生活方式而暴露于阳光下的人尤其严重。全世界的流行病学研究表明，皮肤癌的发病率与紫外线照射有直接联系。皮肤癌是美国高加索人群中最常见的癌症类型;每年诊断出超过50万至1，000，000例病例。美国每年的治疗费用估计在5亿美元到10亿美元之间。这些发现在最大意义上与公共卫生保健直接相关，但关于太阳紫外线照射损害皮肤的机制的知识还远未完成。紫外线照射通过至少两种相互依赖但不同的机制损伤人类皮肤：1）DNA损伤，其导致导致细胞转化的基因突变，和2）信号转导途径的激活，其强烈诱导基质金属蛋白酶和其他基因产物，其促进传导癌症形成的局部组织环境。新出现的证据表明，表皮生长因子受体（EGFR）的酪氨酸磷酸化是紫外线照射刺激诱导基质金属蛋白酶的信号转导途径的主要驱动力。该提案的重点是阐明紫外线照射增加EGFR酪氨酸磷酸化的分子机制。拟议的研究将检验受体型蛋白酪氨酸磷酸酶-k（RPTP-k）特异性使EGFR去磷酸化的假设。通过UV产生的氧化应激对RPTP-k的可逆抑制导致EGFR酪氨酸磷酸化增加，从而驱动下游信号转导途径。提出了四个具体目的：1）确定RPTP-k对EGFR酪氨酸磷酸化和信号传导的调节，2）确定RPTP-k的底物特异性，3）确定RPTP-k的功能结构域，4）确定EGFR和RPTP-k在富含小窝蛋白的膜筏中的共定位在EGFR酪氨酸磷酸化和信号传导调节中的作用。