title: The annexin 2-S100A10 complex and its association with TRPV6 is regulated by cAMP/PKA/CnA in airway and gut epithelia.
abstract: The formation of a heterotetrameric complex between annexin 2 (anx 2) and S100A10 plays an important role in regulating the cellular distribution and biochemical properties of anx 2. A major distinction between the anx 2-S100A10 complex and other annexin-S100 complexes is that S100A10 binding to anx 2 occurs independently of calcium. Here we describe a cyclic 3',5'-adenosine monophosphate (cAMP) and cAMP-dependent protein kinase (PKA, EC 2.7.1.37)-dependent mechanism regulating anx 2-S100A10 complex formation and its interaction with the transient receptor potential vanilloid type 6 channel (TRPV6) in airway and gut epithelia. In both 16HBE14o- and Caco-2 cells, forskolin (FSK) stimulated increased anx 2-S100A10 complex formation, which was attenuated by either PKA inhibitors or calcineurin A (CnA) inhibitors. The anx 2-S100A10 complex association with TRPV6 was dependent on FSK-induced CnA-dependent dephosphorylation of anx 2. Analysis of the significance of the cAMP/PKA/CnA pathway on calcium influx showed that both PKA and CnA inhibitors attenuated Ca(45) uptake in Caco-2, but not 16HBE14o-, cells. Thus, the cAMP/PKA/CnA-induced anx 2-S100A10/TRPV6 complex may require additional factors for calcium influx or play a role independent of calcium influx in airway epithelia. In conclusion, our data demonstrates that cAMP/PKA/CnA signalling is important for anx 2-S100A10 complex formation and interaction with target molecules in both absorptive and secretory epithelia.
authors.affiliation: Academic Unit of Child Health, University of Sheffield, Stephenson Wing, Sheffield Children's Hospital, Sheffield, South Yorkshire S10 2TH, UK.
authors.forename: Lee A
authors.initials: LA
authors.lastname: Borthwick
authors.forename: Andy
authors.initials: A
authors.lastname: Neal
authors.forename: Lynsey
authors.initials: L
authors.lastname: Hobson
authors.forename: Volker
authors.initials: V
authors.lastname: Gerke
authors.forename: Louise
authors.initials: L
authors.lastname: Robson
authors.forename: Richmond
authors.initials: R
authors.lastname: Muimo
mesh_terms: D017306:Annexin A2 / Q000378:metabolism*; D015153:Blotting, Western; D018938:Caco-2 Cells; D019703:Calcineurin / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D000242:Cyclic AMP / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D003600:Cytosol / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism; D020545:Respiratory Mucosa; D012137:Respiratory System / Q000166:cytology / Q000378:metabolism*; D009418:S100 Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D050916:TRPV Cation Channels / Q000378:metabolism*; D000099248:S100 Calcium Binding Protein A10
chemical_list: D017306:Annexin A2; D019703:Calcineurin; D002118:Calcium; D015220:Calcium Channels; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D009418:S100 Proteins; D050916:TRPV Cation Channels; D000099248:S100 Calcium Binding Protein A10; C422827:TRPV6 protein, human