Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.
Prog Mol Biol Transl Sci. 2013;118:395-411. doi: 10.1016/B978-0-12-394440-5.00015-2.
Beyond their well-characterized roles in G protein-coupled receptor desensitization and trafficking, β-arrestins (ARRBs) have been implicated in the regulation of several basic cellular functions, including cell cycle regulation, cell migration, and apoptotic signaling. Nowhere are the data supporting a physiologically relevant role for these arrestin-mediated responses stronger than in cancer. In vitro, ARRBs regulate cell proliferation, promote migration, and transmit anti-apoptotic survival signals by scaffolding cytosolic signaling protein networks and even translocating to the nucleus to directly regulate gene expression. In animal models, ARRB expression affects tumor initiation time, growth rate, vascularization, survival under hypoxic conditions, invasiveness, and metastatic potential. Studies in human cancer patients have demonstrated that dysregulation of ARRB expression, localization, or phosphorylation is associated with more aggressive cancer phenotypes and poorer outcomes in malignancies involving the breast, lung, prostate, brain, and hematologic system. Collectively, these data build a strong case that ARRB-dependent signaling contributes to the cancer phenotype and that the ARRBs may represent novel therapeutic targets in certain malignancies.
除了在 G 蛋白偶联受体脱敏和运输中作用明确之外，β-arrestins（ARRBs）还被认为参与调节多种基本细胞功能，包括细胞周期调节、细胞迁移和凋亡信号。在癌症中，支持这些 ARRB 介导的反应具有生理相关性的证据最为充分。在体外，ARRBs 通过支架细胞溶质信号蛋白网络调节细胞增殖、促进迁移并传递抗凋亡存活信号，甚至转位到细胞核以直接调节基因表达。在动物模型中，ARRBs 的表达影响肿瘤起始时间、生长速度、血管生成、缺氧条件下的存活率、侵袭性和转移潜能。在人类癌症患者中的研究表明，ARRBs 表达、定位或磷酸化的失调与更具侵袭性的癌症表型以及涉及乳腺、肺、前列腺、脑和血液系统的恶性肿瘤的不良预后相关。总的来说，这些数据有力地表明，ARRBs 依赖性信号转导有助于癌症表型，ARRBs 可能代表某些恶性肿瘤的新型治疗靶点。
