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Role of JAK2-PAK1 interaction in prolactin-dependent signaling

JAK2-PAK1 相互作用在催乳素依赖性信号传导中的作用

基本信息

批准号：
8727530
负责人：
MARIA DIAKONOVA
金额：
$ 29.89万
依托单位：
UNIVERSITY OF TOLEDO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8727530
关键词：
Actins Adipocytes Affect Alveolar Anterior Pituitary Gland Apoptosis Astrocytes Basic Science Binding Biological Biological Process Breast Breast Cancer Cell Breast Epithelial Cells CCND1 gene Cancer Center Cancer Research Project Cancer cell line Cell Survival Cells Cellular Morphology Cessation of life Clinical Sciences Columbidae Consult Cyclin D1 Cytokine Receptors Cytoskeleton DNA Sequence Rearrangement Data Development Dissection Endocrine Etiology Event Functional disorder Gene Expression Regulation Genes Genetic Transcription Gland Goals Grant Growth Factor Hormones Human JAK2 gene Lacrimal gland structure Lactation Letters Life Expectancy Ligand Binding Link Liver Location Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Mammary Neoplasms Mammary gland Mediating Membrane Michigan Milk Molecular Molecular Target Multiprotein Complexes Names Normal Cell Oryctolagus cuniculus Ovary Pancreas Pathway interactions Peptide Mapping Pharmaceutical Preparations Phosphorylation Phosphotransferases Physician Executives Pituitary Gland Play Production Prolactin Prolactin Receptor Prostate Protein Tyrosine Kinase Protein-Serine-Threonine Kinases Proteins Receptor Activation Receptor Signaling Recruitment Activity Regulation Research Risk Role Signal Pathway Signal Transduction Signaling Molecule Signaling Protein Specimen Structure of beta Cell of islet Submandibular gland T-Lymphocyte Translational Research Tumorigenicity Tyrosine Tyrosine Phosphorylation United States Universities Woman Work adapter protein autocrine base biological adaptation to stress cancer cell cancer diagnosis cancer type carcinogenesis cell motility cell type design human disease in vivo interest malignant breast neoplasm mammary epithelium mammary gland development medical schools neoplastic cell novel novel therapeutic intervention oncology overexpression protein protein interaction public health relevance receptor receptor binding response tumor tumor progression two-dimensional

项目摘要

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 2008, 40,480 women are expected to die from breast cancer in the U.S. 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 in breast cancer. 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 increase cell motility. In this grant we propose to examine the hypothesis prolactin-dependent JAK2 phosphorylation of PAK1 regulates PAK1 activity. Activated PAK1 regulation of target proteins may depend on phosphorylation events or/and protein-protein interactions, leading to the formation of a multiprotein complex that modulates the actin cytoskeleton, increases cell motility and invasiveness, mediates cyclin D1 gene transcription and affects tumorigenicity of human breast cancer cells. Aim1 will determine the role of JAK2-phosphorylated PAK1 in regulating PRL-dependent actin cytoskeleton rearrangement, cell motility and invasiveness. Aim2 will determine the role of PAK1 in regulating PRL-activated cyclin D1 gene transcription. Finally, Aim3 will determine whether JAK2 phosphorylation of PAK1 affects the tumorigenicity of human breast cancer cells in vivo. 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（由申请方提供）：在正常乳腺发育中，激素催乳素（PRL）对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，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（仅次于肺癌）。2008年，预计美国将有40，480名妇女死于乳腺癌。催乳素受体（PRLR）在80%的人类乳腺癌中被检测到，并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，因此催乳素可作为人乳腺癌细胞的自分泌生长因子。这些结果表明，需要更全面地了解乳腺癌中的PRLR信号。酪氨酸（Tyr）激酶JAK 2被鉴定为PRLR结合的信号分子。对PRLR-JAK 2募集的蛋白质的鉴定和随后被激活的信号通路的解剖将最终为理解PRL作用提供基础。初步数据表明，丝氨酸-苏氨酸激酶PAK 1与JAK 2结合并被JAK 2磷酸化。二维肽图谱鉴定了PAK 1的三个Tyr（s），其被JAK 2磷酸化。JAK 2对PAK 1的Tyr磷酸化也显示出增加细胞运动性。在这项研究中，我们提出了一个假设，即催乳素依赖的JAK 2磷酸化PAK 1调节PAK 1的活性。激活的PAK 1对靶蛋白的调节可能取决于磷酸化事件或/和蛋白质-蛋白质相互作用，导致多蛋白复合物的形成，该复合物调节肌动蛋白细胞骨架，增加细胞运动性和侵袭力，介导细胞周期蛋白D1基因转录并影响人乳腺癌细胞的致瘤性。Aim 1将决定JAK 2磷酸化PAK 1在调节PRL依赖性肌动蛋白细胞骨架重排、细胞运动性和侵袭性中的作用。Aim 2将决定PAK 1在调节PRL激活的细胞周期蛋白D1基因转录中的作用。最后，Aim 3将确定PAK 1的JAK 2磷酸化是否影响体内人乳腺癌细胞的致瘤性。由于PAK 1和PRL都与乳腺癌有关，因此拟议的研究可能最终填补上游PRL-PRLR-JAK 2事件和下游PAK 1依赖性功能之间的现有空白，以了解人类乳腺癌的机制。JAK 2对PAK 1的Tyr磷酸化可能代表了寻找人类乳腺癌病因和治疗的新分子靶点。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

PAK1 regulates breast cancer cell invasion through secretion of matrix metalloproteinases in response to prolactin and three-dimensional collagen IV.

DOI：
10.1210/me.2012-1322
发表时间：
2013-06
期刊：
Molecular endocrinology
影响因子：
0
作者：
Leah C. Rider;Peter O. Oladimeji;M. Diakonova
通讯作者：
Leah C. Rider;Peter O. Oladimeji;M. Diakonova

Tyrosyl phosphorylated serine-threonine kinase PAK1 is a novel regulator of prolactin-dependent breast cancer cell motility and invasion.

DOI：
10.1007/978-3-319-12114-7_5
发表时间：
2015
期刊：
Advances in experimental medicine and biology
影响因子：
0
作者：
Hammer A;Diakonova M
通讯作者：
Diakonova M

A Derivative of Differentiation-Inducing Factor-3 Inhibits PAK1 Activity and Breast Cancer Cell Proliferation.

分化诱导因子 3 的衍生物抑制 PAK1 活性和乳腺癌细胞增殖。

DOI：
10.23937/2378-3419/2/4/1023
发表时间：
2015
期刊：
International journal of cancer and clinical research
影响因子：
0
作者：
Oladimeji,Peter;Kubohara,Yuzuru;Kikuchi,Haruhisa;Oshima,Yoshiteru;Rusch,Courtney;Skerl,Rebekah;Diakonova,Maria
通讯作者：
Diakonova,Maria

Synergistic Activation of ERα by Estrogen and Prolactin in Breast Cancer Cells Requires Tyrosyl Phosphorylation of PAK1.