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）：乳腺癌是女性的主要癌症，是女性癌症死亡的第二大原因。基于当前美国妇女的预期寿命，在她的一生中，有1名女性将患上乳腺癌 - 1960年14岁的风险是14个。肿瘤转移仍然是乳腺癌死亡的主要原因。尽管通过化学疗法和放射疗法，在某些情况下预后有所改善，但这些方法通常会导致严重的副作用。两种蛋白质-JAK2和PAK1 - 伴随乳腺癌。酪氨酸（Tyr）激酶JAK2被鉴定为催乳素受体结合的信号分子。在80％的人乳腺癌中检测到催乳素受体，并在乳腺癌细胞中过表达。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乳腺癌细胞的自分泌生长因子。丝氨酸 - 苏氨酸激酶PAK1通过几种证据与乳腺癌联系在一起：（a）乳腺癌中已经报道了PAK1基因扩增和/或PAK1蛋白上调；（b）激活的PAK1增加了乳腺癌细胞的细胞侵袭；（c）PAK1参与了几种不同的有丝分裂原激活蛋白激酶级联反应的激活或调节，从而导致增殖增加；（d）PAK1通过增强细胞存活而有助于癌性表型。初步数据证明PAK1与JAK2磷酸化并与Tyr磷酸化。二维肽映射确定了三个由JAK2磷酸化的PAK1的Tyr。 JAK2对PAK1的Tyr磷酸化也被证明可保护细胞免受细胞凋亡的影响并增加细胞运动。该赠款建议检验以下假设：PAK1的JAK2依赖性酪酶磷酸化会激活PAK1，增加细胞的增殖，并引起人类乳腺细胞的锚固无关生长和侵入性。 AIM1将通过促进细胞增殖和/或独立的生长来确定PAK1的JAK2磷酸化是否会改变人类乳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/或降低细胞粘附而引起人类乳腺细胞的侵入性。尽管已广泛认识到JAK2和PAK1在乳腺癌中的重要性，但所涉及的机制仍然很少理解。在我们对乳腺癌进展机理的理解中，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是由JAK2磷酸化并参与细胞存活的重要信号分子。拟议研究的结果将提供对JAK2对PAK1酪酶磷酸化的基本机制的重要见解，从而调节细胞增殖和侵入性。它还将提供所需的洞察力，了解JAK2和PAK1参与乳腺癌的可能机制。我们认为，JAK2对PAK1对PAK1的酪酶磷酸化可能代表了寻找人类乳腺癌的神学和治疗的新型分子靶标。公共卫生相关性：乳腺癌是女性最常见的癌症 - 乳腺中所有癌症中近三分之一（30％）的癌症发生。基于当前美国女性的预期寿命，在她的一生中，有1名女性将患上乳腺癌 - 1960年14岁的风险在1960年中有1个。对于正常细胞成为癌细胞的分子生物学机制，仍然未知很多。正常的细胞行为由多个信号通路严格控制，这些信号通路可确保细胞仅在人体要求时增殖。当正常生长调节分解时，发生癌症，通常是由于这些信号传导机制缺陷。实际上，转移是癌症到体内遥远部位的传播，实际上是使癌症如此致命的原因。外科医生可以相对容易去除原发性肿瘤，但是转移的癌症通常到达如此多的地方，仅通过手术治愈就变得不可能。细胞转移的能力也受多个信号通路的调节。两种蛋白质-JAK2和PAK1-与细胞途径的调节有关，这些蛋白可能导致乳腺癌，但它们如何一起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的分子机制，以及导致人类乳腺癌的分子机制。为了实现这一目标，我们已经开始分析JAK2之间的关系和pak1。我们表明JAK2与PAK1结合，并使PAK1更活跃。活化的PAK1有助于更好的细胞存活，从而促进癌症的发展。在当前的建议中，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。在理解这些蛋白质如何共同起作用的过程中，将有助于设计新的治疗方法，并可能使用用于治疗人类乳腺癌的药物。