Function of the PRL Receptor Complex in Breast Cancer

神经内分泌激素催乳素(PRL)是人类乳房重要的生长分化因子。PRL对乳腺问题的这些作用是通过催乳素受体(PRLr)实现的，PRLr是一种I型跨膜受体，是细胞因子受体超家族的成员。在乳房中，表达了四种结构和功能不同的PRLr亚型(长、中、DeltaS1和PRLBP)。PRLr亚型与细胞外配体的结合首先诱导受体二聚化和磷酸化，激活细胞内PRLr相关信号蛋白，触发这些PRLr相关信号网络，促进人乳腺癌细胞的生长和运动。我们的实验室已经证明，PRLR的酪氨酸磷酸化是这些作用所必需的。PRLr的作用也受细胞外基质的刺激，表明整合素和PRLr之间存在信号中介。我们最近证实，跨膜蛋白SHPS1和蛋白酪氨酸磷酸酶(PTP)的复合体SHP1和SHP与deltaS1PRLr结合，并在PRL刺激后经历酪氨酸磷酸化。更多的数据还表明，SHPS1/SHP1/SHP2复合体反过来可以调节相关受体的信号和功能。鉴于这些发现，这一建议的中心假设是PRLR亚型的磷酸化及其与SHPS1/SHP1/SHP2复合体的相互作用有助于人类乳腺癌的体外运动和体内进展。这一假设将通过使用组织培养和人类乳腺癌异种移植模型的三个特定目标来验证。首先，我们将从分子水平探讨PRLr亚型磷酸化的机制及其功能意义。其次，将通过野生型和突变型蛋白的过度表达来评估SHPS1/SHP1/SHP2复合体在PRLr信号转导中的磷酸化、结合和作用。第三，将评估磷酸化的PRLR亚型和SHPS/SHP1/SHP2复合体在乳腺癌运动和转移中的作用。这些研究将深入了解新发现的PRLR亚型和相关的SHPS1复合体的功能，进一步定位PRL在乳房中的功能。对PRLR异构体的这种结构/功能分析最终可能为旨在干扰人类乳腺癌中PRL/PRLr复合体功能的新的治疗策略提供基础。

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.