title: β-arrestin-2 regulation of the cAMP response element binding protein.
abstract: Previous work demonstrated that cystic fibrosis (CF) cells exhibit an increase in cAMP-mediated signaling as a characteristic response to lost CFTR function. Evidence for increased cAMP-mediated signaling in CF included increased phosphorylation of the cAMP response element binding protein (CREB) and elevated β-arrestin-2 (βarr2) expression. However, subsequent studies reveal that CREB activation in CF cells is independent of protein kinase-A (PKA). The goal of this study is to test the hypothesis that elevated βarr2 expression leads to increased CREB activation in a PKA-independent mechanism. βarr2-GFP expressing tracheal epithelial cells (βarr2-GFP) exhibit an increase of pCREB content and subsequent CRE activation compared to GFP expressing control cells. βarr2 activation of the ERK cascade represents a candidate mechanism leading to CREB activation. ERK exhibits increased activation in βarr2-GFP cells compared to cont-GFP cells, and ERK inhibition diminishes CRE activation in both GFP and βarr2-GFP cells. To test directly whether CREB regulation in CF is βarr2-dependent, nasal epithelium excised from wt mice (Cftr +/+; βarr2 +/+), CF mice (Cftr -/-; βarr2 +/+), and DKO mice (Cftr -/-; βarr2 -/-) were analyzed for pCREB protein content. Removal of βarr2 expression from CF mice reduces both pCREB and pERK content to wt levels. These data indicate that CF-related CREB regulation is mediated directly through βarr2 expression via the ERK pathway.
authors.affiliation: Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106-4948, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Manson
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Corey
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Rymut
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kelley
mesh_terms: D000818:Animals; D019390:Arrestins / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D018181:Mice, Inbred CFTR; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010641:Phenotype; D010766:Phosphorylation / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605254:ARRB2 protein, human; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D017362:Cyclic AMP Response Element-Binding Protein; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator