Function of the PRL Receptor Complex in Breast Cancer

PRL 受体复合物在乳腺癌中的功能

• 批准号: 7050107
• 负责人: Charles V Clevenger
• 金额: $ 26.14万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-04-16 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7050107
• 关键词: JAK kinase; MCF7 cell; athymic mouse; biological signal transduction; breast neoplasms; cell motility; dimer; gene expression; guanine nucleotide binding protein; hormone receptor; hormone regulation /control mechanism; human tissue; integrins; ligands; membrane transport proteins; metastasis; neoplastic process; pathologic process; phosphorylation; prolactin; protein isoforms; protein structure function; protein tyrosine phosphatase; receptor binding; receptor expression; site directed mutagenesis

The neuroendocrine hormone prolactin (PRL) is an important growth and differentiation factor for the human breast. The mediation of these effects of PRL on breast issues occurs through the prolactin receptor (PRLr), a Type I transmembrane receptor and member of the cytokine receptor superfamily. Within the breast, four structurally and functionally distinct PRLr isoforms (the long, intermediate, deltaS1, and PRLBP) are expressed. The extracellular binding of ligand by the PRLr isoforms initially induces receptor dimerization and phosphorylation that activates intracellular PRLr-associated signaling proteins The triggering of these PRLr associated signaling networks results in the enhanced growth and motility of human breast cancer cells. Our laboratory has demonstrated that tyrosine phosphorylation of the PRLr is necessary for these actions. PRLr action is also modulated by stimulation with extracellular matrix, indicating the presence of signaling intermediaries between the integrins and the PRLr. We have recently demonstrated that the complex of the transmembrane protein SHPS1 and the protein tyrosine phosphatases (PTP) SHP1 and SHP associate with the deltaS1 PRLr and undergo tyrosine phosphorylation following PRL stimulation. Additional data have also revealed that the SHPS1/SHP1/SHP2 complex, in turn, can modulate the signaling and function of associated receptors. Given these findings, it is the central hypotheses of this proposal that phosphorylation of the PRLr isoforms and their interaction with the SHPS1/SHP1/SHP2 complex contributes to the in vitro motility and in vivo progression of human breast cancer. This hypothesis will be tested by three specific aims using tissue culture and xenograft models of human breast cancer. First, the mechanism and functional significance of PRLr isoform phosphorylation will be examined through molecular approaches. Second, the phosphorylation, association, and role of the SHPS1/SHP1/SHP2 complex during the PRLr signaling will be assessed by over-expression of wild type and mutant forms of these proteins. Third, the role of the phosphorylated PRLr isoforms and the SHPS/SHP1/SHP2 complex to breast cancer motility and metastasis will be evaluated. These studies will provide insight into the function of the newly discovered PRLr isoform and the associated SHPS1 complex, further mapping the function of PRL within the breast. Such structure/function analysis of the PRLr isoforms may ultimately provide the basis for novel therapeutic strategies aimed at interrupting the function of the PRL/PRLr complex in human breast cancer.

神经内分泌激素催乳素（PRL）是人类乳腺的重要生长和分化因子。PRL对乳腺问题的这些作用的介导通过催乳素受体（PRLr）发生，所述催乳素受体是I型跨膜受体和细胞因子受体超家族的成员。 在乳腺内，表达四种结构和功能不同的PRLr亚型（长型、中间型、deltaS 1和PRLBP）。PRLr亚型与配体的细胞外结合最初诱导受体二聚化和磷酸化，其激活细胞内PRLr相关信号传导蛋白。这些PRLr相关信号传导网络的触发导致人乳腺癌细胞的生长和运动性增强。我们的实验室已经证明，PRLr的酪氨酸磷酸化对于这些作用是必要的。PRLr的作用也受到细胞外基质刺激的调节，表明整合素和PRLr之间存在信号传导中介。我们最近已经证明，跨膜蛋白SHPS 1和蛋白酪氨酸磷酸酶（PTP）SHP 1和SHP的复合物与deltaS 1 PRLr相关，并在PRL刺激后进行酪氨酸磷酸化。另外的数据还显示，SHPS 1/SHP 1/SHP 2复合物反过来可以调节相关受体的信号传导和功能。鉴于这些发现，这是该提议的中心假设，即PRLr亚型的磷酸化及其与SHPS 1/SHP 1/SHP 2复合物的相互作用有助于人乳腺癌的体外运动性和体内进展。这一假设将通过三个特定的目标，使用组织培养和异种移植模型的人乳腺癌进行测试。首先，PRLr亚型磷酸化的机制和功能意义将通过分子方法进行研究。第二，将通过这些蛋白的野生型和突变形式的过表达来评估SHPS 1/SHP 1/SHP 2复合物在PRLr信号传导期间的磷酸化、缔合和作用。第三，将评估磷酸化PRLr亚型和SHPS/SHP 1/SHP 2复合物对乳腺癌运动性和转移的作用。这些研究将提供对新发现的PRLr亚型和相关SHPS 1复合物的功能的深入了解，进一步映射PRL在乳腺内的功能。这种结构/功能分析的催乳素受体亚型可能最终提供了新的治疗策略，旨在中断的PRL/催乳素受体复合物在人类乳腺癌的功能的基础。

项目成果

Translocation and action of polypeptide hormones within the nucleus. Relevance to lactogenic transduction.

细胞核内多肽激素的易位和作用。

• DOI: 10.1007/0-306-46832-8_9
• 发表时间: 2000
• 期刊: Advances in experimental medicine and biology
• 作者: Clevenger,CV;Rycyzyn,MA
• 通讯作者: Rycyzyn,MA

Role of cyclophilin B in prolactin signal transduction and nuclear retrotranslocation.

• DOI: 10.1210/mend.14.8.0508
• 发表时间: 2000-08
• 期刊: Molecular endocrinology
• 作者: M. Rycyzyn;Sean C. Reilly;Kerri O’Malley;C. Clevenger

Activation and association of the Tec tyrosine kinase with the human prolactin receptor: mapping of a Tec/Vav1-receptor binding site.

Tec 酪氨酸激酶与人催乳素受体的激活和关联：绘制 Tec/Vav1 受体结合位点。

• DOI: 10.1210/mend.15.5.0631
• 发表时间: 2001
• 期刊: Molecular endocrinology (Baltimore, Md.)
• 作者: Kline,JB;Moore,DJ;Clevenger,CV
• 通讯作者: Clevenger,CV

Negative cross talk between NFAT1 and Stat5 signaling in breast cancer.

• DOI: 10.1210/me.2011-1141
• 发表时间: 2011-09
• 期刊: Molecular endocrinology
• 作者: Jiamao Zheng;Feng Fang;Xianke Zeng;Terry R. Medler;A. Fiorillo;C. Clevenger

Prolactin stimulates ubiquitination, initial internalization, and degradation of its receptor via catalytic activation of Janus kinase 2.

催乳素通过 Janus 激酶 2 的催化激活刺激其受体的泛素化、初始内化和降解。

• DOI: 10.1677/joe-07-0554
• 发表时间: 2008
• 期刊: The Journal of endocrinology
• 作者: Swaminathan,Gayathri;Varghese,Bentley;Thangavel,Chellappagounder;Carbone,ChristopherJ;Plotnikov,Alexander;Kumar,KGSuresh;Jablonski,ElizabethM;Clevenger,CharlesV;Goffin,Vincent;Deng,Luqin;Frank,StuartJ;Fuchs,SergeY
• 通讯作者: Fuchs,SergeY