Role of JAK2-PAK1 interaction in human breast cancer

JAK2-PAK1 相互作用在人类乳腺癌中的作用

基本信息

批准号：
7515304
负责人：
MARIA DIAKONOVA
金额：
$ 21.6万
依托单位：
UNIVERSITY OF TOLEDO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7515304
关键词：
Academic Research Enhancement Awards Adhesions Adverse effects Anchorage-Independent Growth Apoptosis Apoptotic Basic Science Binding Biological Breast Breast Cancer Cell Cancer Etiology Cancer cell line Cancerous Cell Adhesion Cell Proliferation Cell Survival Cell division Cell physiology Cells Cellular Morphology Cessation of life Clinical Cytokine Network Pathway Cytokine Signaling Data Defect Development Distant Docking Ensure Epithelial Cells Etiology Event Family Gene Amplification Goals Grant Growth Growth Factor Human In Vitro JAK2 gene Janus kinase 2 Lead Life Expectancy Ligands Link MAP Kinase Modules Malignant - descriptor Malignant Neoplasms Mammary Neoplasms Mitogen-Activated Protein Kinases Molecular Molecular Target Neoplasm Metastasis Normal Cell Operative Surgical Procedures PTB Domain Pathway interactions Peptide Mapping Pharmaceutical Preparations Phenotype Phosphorylation Primary Neoplasm Prolactin Prolactin Receptor Proliferating Property Protein Overexpression Protein Tyrosine Kinase Protein-Serine-Threonine Kinases Proteins Public Health Radiation therapy Receptor Activation Regulation Reporting Research Risk Role Signal Pathway Signal Transduction Signaling Molecule Site Specimen Surgeon Transcriptional Activation Translations Tumor Cell Line Tumor Tissue Tyrosine Tyrosine Phosphorylation United States Universities Up-Regulation Woman Work autocrine base biological adaptation to stress cancer cell cancer diagnosis cancer type carcinogenesis cell behavior cell motility chemotherapy cytokine design improved insight interest malignant breast neoplasm novel novel therapeutics oncology outcome forecast receptor receptor binding tumor tumor progression two-dimensional

项目摘要

DESCRIPTION (provided by applicant): Breast cancer is the leading type of cancer in women and is the second leading cause of cancer death among women. Based on the current life expectancy for women in the United States, 1 out of 9 women will develop breast cancer in her lifetime - a risk that was 1 out of 14 in 1960. Tumor metastasis still remains the main cause of breast cancer death. Although with chemotherapy and radiation therapy, the prognosis has improved in some cases, these approaches often result in severe side effects. Two proteins - JAK2 and PAK1-have been implicated in breast cancer. Tyrosine (Tyr) kinase JAK2 was identified as a prolactin receptor-bound signaling molecule. The prolactin receptor is detected in 80% of human breast cancers and is overexpressed in breast cancer cells. Normal and tumor mammary epithelial cells synthesize prolactin and prolactin receptor, thus the prolactin could behave as an autocrine growth factor for human breast cancer cells. Serine-threonine kinase PAK1 has been linked to breast cancer by several lines of evidence: (a) PAK1 gene amplification and/or PAK1 protein up-regulation have been reported in breast cancers; (b) activated PAK1 increased cell invasion of breast cancer cells; (c) PAK1 is involved in the activation or regulation of several distinct mitogen-activated protein kinase cascades that lead to increased proliferation; (d) PAK1 contributes towards cancerous phenotypes by enhancement of cell survival. Preliminary data demonstrate that PAK1 associates with and is Tyr phosphorylated by JAK2. Two-dimensional peptide mapping identified three Tyr(s) of PAK1 which are phosphorylated by JAK2. Tyr phosphorylation of PAK1 by JAK2 was also shown to protect cells from apoptosis and increase cell motility. This grant proposes to examine the hypothesis that JAK2-dependent tyrosyl phosphorylation of PAK1 activates PAK1, increases cell proliferation, and causes anchorage-independent growth and invasiveness of human breast cell. Aim1 will determine whether JAK2 phosphorylation of PAK1 alters in vitro growth properties of human breast cells by promoting cells proliferation and/or anchorage-independent growth. Aim2 will determine whether JAK2 phosphorylation of PAK1 causes human breast cell invasiveness by increasing cell motility and/or decreasing cell adhesion. Although the significance of both JAK2 and PAK1 in breast cancer is widely acknowledged, the mechanism involved remains poorly understood. There is a gap between upstream JAK2-dependent events and downstream PAK1 and PAK1-dependent functions in our understanding of the mechanism of breast cancer progression. Exciting preliminary data suggest that PAK1 is an important signaling molecule phosphorylated by JAK2 and participating in cell survival. The results of the proposed studies will provide important insight into the fundamental mechanism by which tyrosyl phosphorylation of PAK1 by JAK2 regulates cell proliferation and invasiveness. It will also provide needed insight into the possible mechanism by which JAK2 and PAK1 participate in breast cancer. We believe that tyrosyl phosphorylation of PAK1 by JAK2 is likely to represent a novel molecular target in the search for theetiology and treatment of human breast cancer. PUBLIC HEALTH RELEVANCE: Breast cancer is the most commonly diagnosed cancer in women - nearly 1 in 3 (30%) of all cancers in women occur in the breast. Based on the current life expectancy for women in the United States, 1 out of 9 women will develop breast cancer in her lifetime - a risk that was 1 out of 14 in 1960. Much is still unknown regarding the molecular biological mechanism by which a normal cell becomes a cancer cell. Normal cell behavior is tightly controlled by multiple signaling pathways that ensure that cells proliferate only when they are required by the body. Cancer occurs when normal growth regulation breaks down, usually because of a defect in these signaling mechanisms. Metastasis, the spread of cancer to distant sites in the body, is in fact what makes cancer so lethal. A surgeon can remove a primary tumor relatively easily, but a cancer that has metastasized usually reaches so many places that cure by surgery alone becomes impossible. The ability of cells to metastasize is also regulated by multiple signaling pathways. Two proteins - JAK2 and PAK1 -have been implicated in the regulation of cell pathways that can lead to breast cancer but how they work together and the precise mechanism of their action is unknown. Our long term goal is to understand the molecular mechanisms that control cell division and cell motility and disregulation of which leads to human breast cancer. Toward this aim, we have started to analyze the relationship between JAK2 and PAK1. We showed that JAK2 binds to PAK1 and makes PAK1 more active. Activated PAK1 contributes to better cell survival that may promote cancer development. In the current proposal we will study how JAK2 and PAK1 increase cell proliferation and cell migration that leads to metastasis. In understanding of how these proteins work together will help to design new therapeutic approaches and possibly drugs for treatment of human breast cancer.

描述（由申请人提供）：乳腺癌是女性癌症的主要类型，也是女性癌症死亡的第二大原因。根据目前美国女性的预期寿命，每 9 名女性中就有 1 人一生中会患乳腺癌——这一风险在 1960 年是每 14 人中就有 1 人罹患乳腺癌。肿瘤转移仍然是乳腺癌死亡的主要原因。尽管通过化疗和放射治疗，某些病例的预后有所改善，但这些方法通常会导致严重的副作用。两种蛋白质 - JAK2 和 PAK1 - 与乳腺癌有关。酪氨酸 (Tyr) 激酶 JAK2 被鉴定为催乳素受体结合信号分子。催乳素受体在 80% 的人类乳腺癌中检测到，并且在乳腺癌细胞中过度表达。正常和肿瘤乳腺上皮细胞合成催乳素和催乳素受体，因此催乳素可以作为人类乳腺癌细胞的自分泌生长因子。多种证据表明丝氨酸-苏氨酸激酶 PAK1 与乳腺癌有关： (a) 据报道，乳腺癌中 PAK1 基因扩增和/或 PAK1 蛋白上调； (b) 激活的PAK1增加乳腺癌细胞的细胞侵袭； (c) PAK1 参与几种不同的丝裂原激活蛋白激酶级联的激活或调节，从而导致增殖增加； (d) PAK1 通过增强细胞存活来促进癌表型。初步数据证明 PAK1 与 JAK2 结合并被 JAK2 磷酸化。二维肽图谱鉴定出 PAK1 的三个酪氨酸被 JAK2 磷酸化。 JAK2 对 PAK1 的 Tyr 磷酸化也被证明可以保护细胞免于凋亡并增加细胞运动性。该资助计划检验以下假设：PAK1 的 JAK2 依赖性酪氨酰磷酸化可激活 PAK1，增加细胞增殖，并导致人类乳腺细胞的贴壁依赖性生长和侵袭性。 Aim1 将确定 PAK1 的 JAK2 磷酸化是否通过促进细胞增殖和/或不依赖贴壁的生长来改变人乳腺细胞的体外生长特性。 Aim2 将确定 PAK1 的 JAK2 磷酸化是否通过增加细胞运动和/或减少细胞粘附而导致人类乳腺细胞侵袭。尽管 JAK2 和 PAK1 在乳腺癌中的重要性已得到广泛认可，但所涉及的机制仍知之甚少。在我们对乳腺癌进展机制的理解中，上游 JAK2 依赖性事件与下游 PAK1 和 PAK1 依赖性功能之间存在差距。令人兴奋的初步数据表明，PAK1 是一种被 JAK2 磷酸化并参与细胞存活的重要信号分子。拟议研究的结果将为了解 JAK2 对 PAK1 酪氨酰磷酸化调节细胞增殖和侵袭的基本机制提供重要见解。它还将为 JAK2 和 PAK1 参与乳腺癌的可能机制提供所需的见解。我们相信，JAK2 对 PAK1 的酪氨酰磷酸化可能代表寻找人类乳腺癌的病因和治疗的新分子靶点。公共卫生相关性：乳腺癌是女性最常诊断出的癌症 - 近三分之一 (30%) 的女性癌症发生在乳房。根据目前美国女性的预期寿命，每 9 名女性中就有 1 人会在一生中患上乳腺癌——这一风险在 1960 年是每 14 人中就有 1 人罹患乳腺癌。关于正常乳腺癌发生的分子生物学机制，目前仍不清楚。细胞变成癌细胞。正常细胞行为受到多种信号通路的严格控制，确保细胞仅在身体需要时才增殖。当正常的生长调节被破坏时，癌症就会发生，通常是因为这些信号机制的缺陷。转移，即癌症扩散到身体的远处部位，实际上是癌症如此致命的原因。外科医生可以相对容易地切除原发肿瘤，但已经转移的癌症通常会扩散到很多地方，仅通过手术治愈是不可能的。细胞转移的能力也受到多种信号通路的调节。两种蛋白质——JAK2和PAK1——与可导致乳腺癌的细胞途径的调节有关，但它们如何协同工作以及其作用的确切机制尚不清楚。我们的长期目标是了解控制细胞分裂和细胞运动及其失调导致人类乳腺癌的分子机制。为了这个目标，我们开始分析JAK2之间的关系和PAK1。我们发现 JAK2 与 PAK1 结合并使 PAK1 更加活跃。激活的 PAK1 有助于更好的细胞存活，从而可能促进癌症的发展。在当前的提案中，我们将研究 JAK2 和 PAK1 如何增加细胞增殖和细胞迁移，从而导致转移。了解这些蛋白质如何协同工作将有助于设计新的治疗方法和可能的治疗人类乳腺癌的药物。