Role of the serine-threonine kinase PAK1 in prolactin-dependent signaling

丝氨酸-苏氨酸激酶 PAK1 在催乳素依赖性信号传导中的作用

• 批准号: 7275223
• 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
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7275223
• 关键词: Role; serine; threonine; kinase; PAK1

DESCRIPTION (provided by applicant): In normal mammary development, the hormone prolactin (PRL) is critical for alveolar proliferation and differentiation. Increasing evidence supports the involvement of PRL in breast cancer, the leading type of cancer in women and the second leading cause (after lung cancer) of cancer death among women. In 2002, 203,500 new cases of breast cancer were expected to be diagnosed, and 39,600 women were expected to die of the disease. The prolactin receptor (PRLR) is detected in 80% of human breast cancers, and is overexpressed in breast cancer cells. Normal and tumor mammary epithelial cells synthesize PRL and PRLR, thus the PRL could behave as an autocrine growth factor for human breast cancer cells. These results suggest the need for a more complete understanding of PRLR signaling to growth promoting, anti-apoptotic pathways. Tyrosine (Tyr) kinase JAK2 was identified as a PRLR-bound signaling molecule. Identification of the proteins recruited to the PRLR-JAK2 and dissection of the signaling pathways that are subsequently activated will ultimately provide a basis for understanding PRL action. Preliminary data demonstrate that the serine-threonine kinase 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. This grant proposes to examine the hypothesis that PAK1 is a substrate for JAK2 and that in response to PRL, PAK1 is activated by JAK2-dependent Tyr phosphorylation and enhances PRL-dependent cell survival. Aim1 will verify that PRL promotes Tyr phosphorylation of PAK1 in vivo. Aim2 will determine whether JAK2 phosphorylation of PAK1 alters PAK1 kinase activity and/or ability of PAK1 to bind PAK1 targets. In Aim3 the effect of JAK2 Tyr phosphorylation of PAK1 on PRL-dependent cell survival will be determined. Because both PAK1 and PRL have been implicated in breast cancer, the proposed studies may ultimately fill out the existing gap between upstream PRL-PRLR-JAK2 events and downstream PAK1-dependent functions in our understanding of the mechanism of human breast cancer. Tyr phosphorylation of PAK1 by JAK2 is likely to represent a novel molecular target in the search for the etiology and treatment of human breast cancer.

描述（由申请人提供）：在正常的乳腺发育中，激素催乳素（PRL）对于肺泡增殖和分化至关重要。越来越多的证据支持PRL参与乳腺癌，女性的主要癌症类型，以及妇女中癌症死亡的第二大主要原因（肺癌之后）。 2002年，预计将诊断出203,500例新的乳腺癌病例，预计有39,600例妇女死于该疾病。在80％的人乳腺癌中检测到催乳素受体（PRLR），并在乳腺癌细胞中过表达。正常和肿瘤乳腺上皮细胞合成PRL和PRLR，因此PRL可以作为人类乳腺癌细胞的自分泌生长因子。这些结果表明，需要更完整地了解PRLR信号传导，以促进生长，抗凋亡途径。酪氨酸（Tyr）激酶JAK2被鉴定为PRLR结合的信号分子。鉴定募集到PRLR-JAK2的蛋白质和随后激活的信号通路的解剖最终将为理解PRL作用提供基础。初步数据表明，丝氨酸 - 硫代激酶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凋亡。该赠款提出了以下假设：PAK1是JAK2的底物，并且在响应PRL时，PAK1被JAK2依赖性的Tyr磷酸化激活并增强了PRL依赖性细胞的存活。 AIM1将验证PRL在体内促进PAK1的Tyr磷酸化。 AIM2将确定PAK1的JAK2磷酸化是否会改变PAK1激酶活性和/或PAK1结合PAK1靶标的能力。在AIM3中，将确定PAK1的JAK2 TYR磷酸化对PRL依赖性细胞存活的影响。由于PAK1和PRL都与乳腺癌有关，因此提出的研究最终可能填补了上游PRL-PRLR-JAK2事件与下游PAK1依赖性功能之间现有的差距，这在我们对人类乳腺癌机制的理解中的理解。 JAK2对PAK1的Tyr磷酸化可能代表着寻找人类乳腺癌病因和治疗的新分子靶标。