Biological activity of free arrestins is often overlooked. Based on available data, we compare arrestin-mediated signaling that requires and does not require binding to G-protein-coupled receptors (GPCRs). Receptor-bound arrestins activate ERK1/2, Src, and focal adhesion kinase (FAK). Yet, arrestin-3 regulation of Src family member Fgr does not appear to involve receptors. Free arrestin-3 facilitates the activation of JNK family kinases, preferentially binds E3 ubiquitin ligases Mdm2 and parkin, and facilitates parkin-dependent mitophagy. The binding of arrestins to microtubules and calmodulin and their function in focal adhesion disassembly and apoptosis also do not involve receptors. Biased GPCR ligands and the phosphorylation barcode can only affect receptor-dependent arrestin signaling. Thus, elucidation of receptor dependence or independence of arrestin functions has important scientific and therapeutic implications.

游离视紫红质抑制蛋白的生物活性常常被忽视。根据现有数据，我们比较了需要和不需要与 G 蛋白偶联受体 (GPCR) 结合的抑制蛋白介导的信号传导。受体结合的抑制蛋白激活 ERK1/2、Src 和粘着斑激酶 (FAK)。然而，抑制蛋白-3 对 Src 家族成员 Fgr 的调节似乎并不涉及受体。游离的抑制蛋白-3 促进 JNK 家族激酶的激活，优先结合 E3 泛素连接酶 Mdm2 和 Parkin，并促进 Parkin 依赖性线粒体自噬。视紫红质抑制蛋白与微管和钙调蛋白的结合及其在粘着斑分解和细胞凋亡中的功能也不涉及受体。偏向的 GPCR 配体和磷酸化条形码只能影响受体依赖性抑制蛋白信号传导。因此，阐明抑制蛋白功能的受体依赖性或独立性具有重要的科学和治疗意义。