Paxillin as a Liaison between Extranuclear and Intranuclear Steroid Signaling

桩蛋白作为核外和核内类固醇信号传导之间的联络者

• 批准号: 8445552
• 负责人: STEPHEN R. HAMMES
• 金额: $ 29.17万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445552
• 关键词: Agonist; Androgen Receptor; Androgens; Binding; Binding Proteins; Biological Process; Cancer Cell Growth; Cancer Patient; Castration; Cell Nucleus; Cell Proliferation; Cell membrane; Cell surface; Communication; Complex; Cyclin D1; Cytoplasm; Data; Diagnostic; EGF gene; Epidermal Growth Factor Receptor; Event; Gene Expression; Genes; Genetic Transcription; Genomics; Growth; Growth Factor; Human; Laboratory Study; Malignant neoplasm of prostate; Mediating; Mediator of activation protein; Membrane; Nuclear; PC3 cell line; Patients; Peptides; Phosphorylation; Phosphoserine; Phosphotransferases; Physiological; Proliferating; Prostate; Proteins; Proteomics; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Relative (related person); Research Personnel; Role; Sampling; Serine; Serine Phosphorylation Site; Signal Pathway; Signal Transduction; Small Interfering RNA; Steroid Receptors; Steroids; Techniques; Technology; Testing; Tissue Microarray; Tissues; Transactivation; Travel; Tumor Cell Line; Xenograft Model; Xenograft procedure; cancer cell; castration resistant prostate cancer; design; in vivo; member; migration; non-genomic; novel; paxillin; prevent; prostate cancer cell; prostate cancer model; protein purification; public health relevance; research study; response; therapeutic target; tumor; tumor growth

DESCRIPTION (provided by applicant): Researchers have known for decades that signaling events in the cytoplasm can have profound effects on signaling events in the nucleus; however details regarding how this cytoplasm to nuclear ("outside-inside") cross talk is regulated are stil not known. We have recently discovered that paxillin, a molecule best known for regulating cytoskeletal remodeling, is a critical liaison between extranuclear and intranuclear signaling in prostate cancer cells. Specifically, we find that paxillin is necessary for extranuclear Erk activation in response to multiple inputs, including nongenomic androgen signaling via membrane-localized androgen receptors (ARs) as well as growth factors via Receptor Tyrosine Kinases (RTKs). Once activated, Erk then regulates phosphorylation of paxillin on serine residues, at which point phosphoserine-paxillin travels to the nucleus and mediates AR- and Erk-dependent transcription. In fact, if we prevent this Erk-mediated phosphorylation of paxillin, then paxillin will not enter the nucleus, androgen and growth factor-dependent transcription is abrogated, and prostate cancer cells do not proliferate in response to any of these agonists. Importantly, we find that cytoplasmic paxillin and nuclear phosphoserine-paxillin expression are upregulated in human prostate cancer relative to normal prostate tissue, implying that paxillin is over-active in tumors. Together, our data suggest that paxillin might be a key mediator of prostate cancer growth and therefore a viable diagnostic and therapeutic target. Furthermore, since paxillin actually regulates Erk activation and downstream effects in every tumor cell line tested, regardless of origin, we postulate that paxillin might be a general regulator of Erk action well beyond the prostate. In this proposal, we will continue to focus on prostate cancer models to further elucidate how paxillin regulates "outside-inside" signaling in response to growth factors, androgens, and other steroids. In addition, we will examine paxillin effects on prostate cancer growth in-vivo, and will more closely examine paxillin expression and activation in human prostate cancer. Finally, we will test novel means of specifically regulating paxillin's actions in the nucleus while sparing it's actions in the cytoplasm, thereby using nuclear paxillin as a target for the treatment of both castration-sensitive and castration-resistant prostate cancer growth.

描述（由申请人提供）：几十年来，研究人员已经知道细胞质中的信号传导事件可以对细胞核中的信号传导事件产生深远的影响;然而，关于如何调节这种细胞质与细胞核（“外-内”）串扰的细节仍然未知。我们最近发现，桩蛋白，一个分子最有名的调节细胞骨架重塑，是一个关键的联络之间的细胞核和核内信号在前列腺癌细胞。具体来说，我们发现桩蛋白是必要的，为细胞核Erk激活响应于多种输入，包括非基因组雄激素信号通过膜定位的雄激素受体（AR）以及生长因子通过受体酪氨酸激酶（RTK）。一旦被激活，Erk然后调节丝氨酸残基上桩蛋白的磷酸化，此时磷酸丝氨酸-桩蛋白行进到细胞核并介导AR和Erk依赖性转录。事实上，如果我们阻止这种ERK介导的桩蛋白磷酸化，那么桩蛋白将不会进入细胞核，雄激素和生长因子依赖性转录被废除，前列腺癌细胞不会对这些激动剂中的任何一种做出反应而增殖。重要的是，我们发现相对于正常前列腺组织，细胞质桩蛋白和核磷酸丝氨酸-桩蛋白表达在人前列腺癌中上调，这意味着桩蛋白在肿瘤中过度活跃。总之，我们的数据表明桩蛋白可能是前列腺癌生长的关键介质，因此是可行的诊断和治疗靶点。此外，由于桩蛋白实际上调节Erk激活和下游效应，在每一个肿瘤细胞系测试，无论起源，我们假设桩蛋白可能是一个一般的调节Erk行动远远超出前列腺。 在这项提案中，我们将继续专注于前列腺癌模型，以进一步阐明桩蛋白如何调节“外-内”信号传导，以响应生长因子，雄激素和其他类固醇。此外，我们将研究桩蛋白对体内前列腺癌生长的影响，并将更密切地研究桩蛋白在人前列腺癌中的表达和激活。最后，我们将测试特异性调节桩蛋白在细胞核中的作用而不影响其在细胞质中的作用的新方法，从而使用细胞核桩蛋白作为治疗去势敏感性和去势抵抗性前列腺癌的靶点 增长