Regulation of somatostatin receptor signaling by receptor interacting proteins.

 描述（由申请人提供）：G蛋白偶联受体家族的细胞表面表达、细胞内运输和信号转导受到与受体胞质结构域相互作用的许多蛋白质的严格调控。这些受体相互作用蛋白（RIP）的突变或改变的表达破坏了锚受体及其效应物的复合物，从而干扰受体定位、运输和稳定性，并导致受体信号传导缺陷。几种RIP已显示与sst 2A生长抑素（SS）受体结合，SS类似物用作垂体和其他激素分泌神经内分泌肿瘤的主要药物治疗的治疗靶点。SS类似物减缓肿瘤进展并抑制生物活性肿瘤产物的分泌，从而控制由激素分泌肿瘤产生的衰弱和潜在危及生命的症状。不幸的是，SS类似物不能控制大部分患者的激素分泌过多。引起患者对SS类似物治疗反应性变化的因素尚不清楚，但不是由sst 2A受体突变引起的，也不能用sst 2A mRNA表达的缺失来解释。本申请的基本假设是，sst 2A受体相互作用蛋白在激素分泌肿瘤对SS类似物的反应性中起关键作用，并且这些蛋白与sst 2A受体的相互作用是动态调节的。在这项提议中，我们计划鉴定垂体瘤细胞中与sst 2A受体相关的蛋白质，并表征所鉴定的相互作用对sst 2A受体的细胞表面表达、其细胞内运输的功能后果。 和稳定性，以及其激活已知介导SS抑制垂体激素分泌的信号转导途径的能力。此外，我们将确定如何在细胞表面和内吞隔室的sst2A受体及其相互作用的合作伙伴之间的关联是动态调节。这些研究将为控制sst 2A受体信号转导、转运和表达的分子机制提供新的认识。此外，我们的研究结果将产生候选蛋白，其基本功能可能在激素分泌肿瘤中受到干扰，从而导致对SS类似物治疗的抵抗。最后，他们可能建议潜在的药物靶点，这些药物作用于sst 2A受体的下游，以绕过受体信号传导的缺陷，从而改善对垂体瘤激素分泌过多的控制。

 DESCRIPTION (provided by applicant): The cell surface expression, intracellular trafficking, and signal transduction by the family of G protein coupled receptors is tightly regulated by numerous proteins that interact with receptor cytoplasmic domains. Mutations in or altered expression of these receptor interacting proteins (RIPs) disrupt the complexes that anchor the receptor and its effectors and thus perturb receptor localization, trafficking and stability and cause defective receptor signaling. Several RIPs have been shown to bind to the sst2A somatostatin (SS) receptor, the therapeutic target for the SS analogs used as primary medical therapy for pituitary and other hormone secreting neuroendocrine tumors. SS analogs slow tumor progression and inhibit the secretion of bioactive tumor products thereby controlling the debilitating and potentially life-threatening symptoms produced by hormone secreting tumors. Unfortunately, SS analogs fail to control hormone hyper-secretion in a large fraction of patients. The factors that cause variability in patient responsiveness to SS analog therapy are not understood but do not result from mutations in the sst2A receptor and cannot be explained by an absence of sst2A mRNA expression. The fundamental hypothesis for this application is that sst2A receptor interacting proteins play a critical role in the responsiveness of hormone secreting tumors to SS analogs and that the interaction of these proteins with the sst2A receptor is dynamically regulated. In this proposal we plan to identify proteins associated with the sst2A receptor in pituitary tumor cells and characterize the functional consequences of the identified interactions on the cell surface expression of the sst2A receptor, on its intracellular trafficking and stability, and on its ability to activate the signal transduction pathways known to mediate SS inhibition of pituitary hormone secretion. In addition, we will determine how the association between the sst2A receptor and its interacting partners is dynamically regulated both at the cell surface and within endocytic compartments. The proposed studies will provide new understanding into the molecular mechanisms that control sst2A receptor signaling, trafficking and expression. Moreover, our results will generate protein candidates whose essential functions may be perturbed in hormone secreting tumors and thus contribute to resistance to SS analog therapy. Finally, they may suggest potential targets for drugs that act downstream of the sst2A receptor to bypass defects in receptor signaling and thus allow improved control of hormonal hypersecretion by pituitary tumors.