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: 6724788
• 负责人: Charles V Clevenger
• 金额: $ 28.21万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 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 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6724788
• 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）是人类乳房重要的生长和分化因子。 PRL 对乳房问题的这些影响是通过催乳素受体 (PRLr) 介导的，PRLr 是一种 I 型跨膜受体，也是细胞因子受体超家族的成员。 在乳房内，表达四种结构和功能不同的 PRLr 同工型（长、中间、deltaS1 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，从而激活细胞内 PRLr 相关信号蛋白。这些 PRLr 相关信号网络的触发导致人乳腺癌细胞的生长和运动增强。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体。我们最近证明，跨膜蛋白 SHPS1 和蛋白酪氨酸磷酸酶 (PTP) SHP1 和 SHP 的复合物与 deltaS1 PRLr 结合，并在 PRL 刺激后发生酪氨酸磷酸化。其他数据还表明，SHPS1/SHP1/SHP2 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，该提案的核心假设是 PRLr 同工型的磷酸化及其与 SHPS1/SHP1/SHP2 复合物的相互作用有助于人乳腺癌的体外运动和体内进展。该假设将通过三个特定目标使用人类乳腺癌的组织培养和异种移植模型进行测试。首先，将通过分子方法研究 PRLr 亚型磷酸化的机制和功能意义。其次，SHPS1/SHP1/SHP2 复合物在 PRLr 信号传导过程中的磷酸化、关联和作用将通过这些蛋白质的野生型和突变型的过表达来评估。第三，将评估磷酸化 PRLr 亚型和 SHPS/SHP1/SHP2 复合物对乳腺癌运动和转移的作用。这些研究将深入了解新发现的 PRLr 亚型和相关 SHPS1 复合物的功能，进一步绘制乳腺内 PRL 的功能。 PRLr亚型的这种结构/功能分析最终可能为旨在中断人乳腺癌中PRL/PRLr复合物的功能的新治疗策略提供基础。