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First published online January 10, 2007
doi: 10.1242/10.1242/jcs.03338

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-arrestin signaling and regulation of transcription

¹ Pharmacology Research Center, Shanghai Medical College and Institutes of Brain Science, Fudan University, 138 Yi Xue Yuan Road, Shanghai 200032, China
² Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Science, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China

View larger version (43K): [in this window] [in a new window]   Fig. 1. Basic scheme for -arrestin negative feedback and GPCR endocytosis. Agonist exposure stimulates activation of GPCR, which leads to the dissociation of G proteins into activated subunit and dimers and triggers the activation of various effectors, such as adenylate cyclase and phospholipase C. The agonist-occupied GPCR is phosphorylated by GRKs, leading to signal desensitization, binding of -arrestin to the activated, phosphorylated GPCR and subsequent endocytosis of the receptor.

View larger version (15K): [in this window] [in a new window]   Fig. 2. Domain structure of -arrestins, showing binding sites and nuclear localization and nuclear export (NES) signals. -arrestins contain two major domains: an N domain and a C domain. The N domain (1-185) is indispensable for the nuclear localization of both -arrestins, and a functional NES (VxxxFxxLxL) is located at the C-terminus of -arrestin 2. The LIEF-binding motif for clathrin and the RxR-binding motif for AP2 within the C-terminus of -arrestins allow them to initiate clathrin-dependent endocytosis. The IP6-binding site resides in the C domain (233-251). The binding regions for Src (1-185), MDM2 (1-186), JNK3 (RRS sequence), IB (1-240) and TRAF6 are shown.

View larger version (47K): [in this window] [in a new window]   Fig. 3. A model for -arrestin-mediated regulation of transcription. (a) Direct pathway. In response to receptor activation, -arrestins translocate from the cytoplasm to the nucleus and associate with transcription cofactors such as p300 and CREB at the promoters of target genes to promote transcription directly. (b) Indirect pathway. -arrestins interact with regulators of transcription factors such as IB and MDM2 in the cytoplasm, which results in changes in activity and the subcellular distribution of these binding partners, and thus exert regulatory effects on the activation of transcription factors indirectly. Ub, ubiquitylation.

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