Role of ?-arrestins in the activation and targeting of MAP kinases
The binding of ?-arrestins to agonist-occupied GPCRs triggers the assembly of a MAP kinase activation complex using ?-arrestin as a scaffold, with subsequent activation of a ?-arrestin-bound pool of ERK1/2. The receptor—?-arrestin—ERK complexes are localized to endosomal vesicles, and their formation does not result in nuclear translocation of activated ERK1/2 or stimulation of cell proliferation. The function of ?-arrestin-bound ERK1/2 is presently unknown. Activation of ERK1/2 by ?-arrestin scaffolds may favor the phosphorylation of plasma membrane, cytosolic, or cytoskeletal ERK1/2 substrates, or it may lead to transcriptional activation through the ERK-dependent activation of other kinases. The model depicts ?-arrestin scaffolding of the ERK1/2 MAP kinase cascade, based upon data obtained with the protease-activated PAR2 and angiotensin AT1a receptors. A similar mechanism has been proposed for regulation of the JNK3 MAP kinase cascade by AT1a receptors.
Contributor: Kosi Gramatikoff, PhD
REFERENCES: Andrew J et al. Physiological Regulation of G Protein-Linked Signaling Physiol Rev, Oct 1999; 79: 1373 - 1430. K. Palczewski. Structure and functions of arrestins Protein Sci., Sep 1994; 3: 1355 - 1361. KL Pierce and RJ Lefkowitz. Classical and new roles of beta-arrestins in the regulation of G-protein-coupled receptors. Nat Rev Neurosci, Oct 2001; 2(10): 727-33. Moritz Bünemann and M. Marlene Hosey. G-protein coupled receptor kinases as modulators of G-protein signaling J. Physiol., May 1999; 517: 5 - 23. Robert J. Lefkowitz. G Protein-coupled Receptors. III. New roles for receptor kinases and -arrestins in receptor signaling and desensitization. J. Biol. Chem., Jul 1998; 273: 18677 - 18680.
-
科技前沿
