Adenylate cyclase regulation via proteasome-mediated modulation of Galphas levels

Cellular Signalling
Silvio NaviglioGennaro Illiano

Abstract

The adenylate cyclase (AC)/cyclic AMP (cAMP)/cAMP-dependent protein kinase pathway controls many biological phenomena. The ubiquitin/proteasome system, controlling the levels of many proteins, modulates important cellular processes such as cell cycle and cell growth. Here we describe a novel mechanism for AC regulation by proteasome pathway. Pharmacological inhibition of proteasome function in human osteosarcoma U2OS cells results in up-regulation of AC activity, increase of levels of alpha subunit of heterotrimeric stimulatory GTP-binding proteins (alphas) and, remarkably, also in preventing of beta-adrenergic receptor-mediated down-regulation of alphas protein levels. Accumulation of alphas protein is also accompanied by the appearance of polyubiquitinated alphas species. Our results: (1) identify alphas protein as a novel proteasome substrate in mammalian cells; (2) indicate that proteasome might play a physiological role in controlling AC/cAMP mediated pathways by modulating the levels of Galphas protein; (3) suggest a role for the proteasome also in controlling alphas-mediated signaling pathways other than those affecting AC complex.

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Citations

Jun 21, 2011·The Journal of Biological Chemistry·Ming ZhuYuqi Wang
Oct 17, 2012·The Journal of Biological Chemistry·Prabha ChandrasekaranSundararajan Venkatesan
Jan 30, 2009·The Journal of Biological Chemistry·Matthew P TorresHenrik G Dohlman
Feb 24, 2007·Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research·S NaviglioM Caraglia
Sep 22, 2009·Cardiovascular Research·Karl Stangl, Verena Stangl
Apr 28, 2007·Circulation Research·Sudha K Shenoy
Mar 9, 2013·Molecular Endocrinology·Verónica Alonso, Peter A Friedman
Oct 19, 2013·Genes to Cells : Devoted to Molecular & Cellular Mechanisms·Riris I JenieHiroshi Itoh
May 15, 2013·Biochemical and Biophysical Research Communications·Kanako ChishikiHideki Sumimoto
Dec 10, 2008·Expert Opinion on Therapeutic Targets·Silvio NaviglioGennaro Illiano
Mar 23, 2006·Journal of Cellular Biochemistry·Silvio NaviglioGennaro Illiano
May 17, 2019·Neuroscience and Biobehavioral Reviews·Fiona LimanaqiFrancesco Fornai

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