Adenylate cyclase regulation via proteasome-mediated modulation of Galphas levels.
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.
Naviglio
Silvio
S
Department of Biochemistry and Biophysics, Second University of Naples, Via L. De Crecchio 7, 80138 Napoli, Italy.
Pagano
Mario
M
Romano
Maria
M
Sorrentino
Annunziata
A
Fusco
Anna
A
Illiano
Fausto
F
Chiosi
Emilio
E
Spina
Annamaria
A
Illiano
Gennaro
G
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism*; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D004791:Enzyme Inhibitors; D061988:Proteasome Inhibitors; D011943:Receptors, Adrenergic, beta; D025801:Ubiquitin; D000242:Cyclic AMP; D046988:Proteasome Endopeptidase Complex; D019205:GTP-Binding Protein alpha Subunits, Gs; D000262:Adenylyl Cyclases