![]() Involved in attenuation of NF-kappa-B-dependent transcription in response to GPCR or cytokine stimulation by interacting with and stabilizing CHUK. Appears to function as signaling scaffold involved in regulation of MIP-1-beta-stimulated CCR5-dependent chemotaxis. Involved in AGTR1-mediated stress fiber formation by acting together with GNAQ to activate RHOA. Involved in F2RL1-mediated cytoskeletal rearrangement and chemotaxis. Involved in activation of the p38 MAPK signaling pathway and in actin bundle formation. Is involved in IGF1-stimulated AKT1 signaling leading to increased protection from apoptosis. Is involved in alpha-thrombin-stimulated AKT1 signaling. Acts as signaling scaffold for the AKT1 pathway. Is involved in proteinase-activated F2RL1-mediated ERK activity. ![]() Is required for SP-stimulated endocytosis of NK1R and recruits c-Src/SRC to internalized NK1R resulting in ERK1/2 activation, which is required for the antiapoptotic effects of SP. Inhibits ERK1/2 signaling in AGTR1- and AVPR2-mediated activation (reciprocal regulation). For some GPCRs the beta-arrestin-mediated signaling relies on either ARRB1 or ARRB2 and is inhibited by the other respective beta-arrestin form (reciprocal regulation). GPCRs for which the beta-arrestin-mediated signaling relies on both ARRB1 and ARRB2 (codependent regulation) include ADRB2, F2RL1 and PTH1R. Recruits c-Src/SRC to ADRB2 resulting in ERK activation. ![]() ERK1/2 activated by the beta-arrestin scaffold is largely excluded from the nucleus and confined to cytoplasmic locations such as endocytic vesicles, also called beta-arrestin signalosomes. Acts as signaling scaffold for MAPK pathways such as MAPK1/3 (ERK1/2). Beta-arrestins function as multivalent adapter proteins that can switch the GPCR from a G-protein signaling mode that transmits short-lived signals from the plasma membrane via small molecule second messengers and ion channels to a beta-arrestin signaling mode that transmits a distinct set of signals that are initiated as the receptor internalizes and transits the intracellular compartment. Involved in the degradation of cAMP by recruiting cAMP phosphodiesterases to ligand-activated receptors. Involved in phopshorylation-dependent internalization of OPRD1 ands subsequent recycling. Involved in internalization of P2RY4 and UTP-stimulated internalization of P2RY2. Receptor resensitization then requires that receptor-bound arrestin is removed so that the receptor can be dephosphorylated and returned to the plasma membrane. Class B receptors, like AVPR2, AGTR1, NTSR1, TRHR and TACR1 internalize as a complex with arrestin and traffic with it to endosomal vesicles, presumably as desensitized receptors, for extended periods of time. ![]() Class A receptors, like ADRB2, OPRM1, ENDRA, D1AR and ADRA1B dissociate from beta-arrestin at or near the plasma membrane and undergo rapid recycling. Two different modes of arrestin-mediated internalization occur. Internalized arrestin-receptor complexes traffic to intracellular endosomes, where they remain uncoupled from G-proteins. However, the extent of beta-arrestin involvement appears to vary significantly depending on the receptor, agonist and cell type. The beta-arrestins target many receptors for internalization by acting as endocytic adapters (CLASPs, clathrin-associated sorting proteins) and recruiting the GPRCs to the adapter protein 2 complex 2 (AP-2) in clathrin-coated pits (CCPs). During homologous desensitization, beta-arrestins bind to the GPRK-phosphorylated receptor and sterically preclude its coupling to the cognate G-protein the binding appears to require additional receptor determinants exposed only in the active receptor conformation. Functions in regulating agonist-mediated G-protein coupled receptor (GPCR) signaling by mediating both receptor desensitization and resensitization processes.
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