title: Unbiased identification of substrates for the Epac1-inducible E3 ubiquitin ligase component SOCS-3.
abstract: The anti-inflammatory effects of the prototypical second messenger cAMP have been extensively documented in multiple cell types. One mechanism by which these effects are achieved is via Epac1 (exchange protein directly activated by cAMP 1)-dependent induction of SOCS-3 (suppressor of cytokine signalling 3), which binds and inhibits specific class I cytokine receptors. One important aspect of SOCS-3 functionality is its role as the specificity determinant within an E3 ubiquitin ligase complex which targets cellular substrates for polyubiquitylation and proteasomal degradation. In the present review, we describe key inhibitory processes that serve to reduce cytokine receptor signalling, focusing primarily on SOCS protein function and regulation. We also outline a strategy we have developed to identify novel ubiquitylated substrates for the Epac1-inducible SOCS-3 E3 ubiquitin ligase complex following purification of the ubiquitinome. It is anticipated that identifying substrates for the Epac1-regulated SOCS-3 E3 ubiquitin ligase, and assessment of their functional significance, may pinpoint new sites for therapeutic intervention that would achieve therapeutic efficacy of cAMP-elevating drugs while minimizing the adverse effects usually associated with these agents.
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, UK.
authors.forename: Jamie J L
authors.initials: JJ
authors.lastname: Williams
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Palmer
mesh_terms: D000818:Animals; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000378:metabolism; D013379:Substrate Specificity; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D057149:Ubiquitinated Proteins / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D021122:Protein Subunits; C116122:RAPGEF3 protein, human; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D057149:Ubiquitinated Proteins; D044767:Ubiquitin-Protein Ligases