Function of the PRL Receptor Complex in Breast Cancer

神经内分泌激素催乳素（PRL）是乳腺重要的生长分化因子。泌乳素受体（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，有四种结构和功能不同的PRLr亚型（long, intermediate， deltaS1和PRLBP）表达。PRLr异构体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类乳腺癌细胞的生长和运动增强。我们的实验室已经证明PRLr的酪氨酸磷酸化是这些作用所必需的。PRLr的作用也可以通过细胞外基质的刺激来调节，这表明在整合素和PRLr之间存在信号中介。我们最近证明了跨膜蛋白SHPS1和蛋白酪氨酸磷酸酶（PTP） SHP1和SHP的复合物与deltaS1 PRLr相关，并在PRL刺激后发生酪氨酸磷酸化。其他数据还显示，SHPS1/SHP1/SHP2复合体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，本研究的核心假设是PRLr亚型的磷酸化及其与SHPS1/SHP1/SHP2复合物的相互作用有助于人类乳腺癌的体外运动和体内进展。这一假设将通过组织培养和人类乳腺癌异种移植模型的三个特定目标进行验证。首先，通过分子途径研究PRLr异构体磷酸化的机制和功能意义。其次，在PRLr信号传导过程中，SHPS1/SHP1/SHP2复合物的磷酸化、关联和作用将通过这些蛋白的野生型和突变型的过度表达来评估。第三，评估磷酸化PRLr亚型和SHPS/SHP1/SHP2复合物在乳腺癌运动和转移中的作用。这些研究将为新发现的PRLr异构体和相关的SHPS1复合物的功能提供深入的了解，进一步绘制PRL在乳腺中的功能。这种PRLr同工型的结构/功能分析可能最终为旨在中断PRL/PRLr复合物在人类乳腺癌中的功能的新治疗策略提供基础。

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.