title: The large isoforms of A-kinase anchoring protein 18 mediate the phosphorylation of inhibitor-1 by protein kinase A and the inhibition of protein phosphatase 1 activity.
abstract: Inhibitor-1 (I-1) is phosphorylated on threonine residue 35 (Thr35) by the cAMP-dependent protein kinase (PKA), inducing the potent inhibition of the serine-threonine-specific protein phosphatase 1 (PP1). We now report that the formation of a signaling complex containing PKA and I-1 by the A-kinase anchoring protein 18 (AKAP18) facilitates this regulation in cells. AKAP18 directly bound I-1, and AKAP18/I-1 complexes were isolated from both rat heart extract and transfected heterologous cells. It is noteworthy that prevention of PKA binding to the AKAP18 scaffold decreased I-1 phosphorylation by 48% in cells. Moreover, the I-1 target PP1 was also associated with AKAP18 complexes. The cAMP-mediated inhibition of phosphatase activity was contingent on PKA binding to the scaffold. These observations reveal an additional level of complexity in PP1 regulation because of its association with AKAP18 multimolecular signaling complexes and suggest that targeting of AKAP18 complexes may be an alternative method to alter phosphatase activity and modulate specific substrate dephosphorylation.
authors.affiliation: Pat and Jim Calhoun Center for Cardiology, University of Connecticut Health Center, Farmington, CT 06032, USA.
authors.forename: Arpita
authors.initials: A
authors.lastname: Singh
authors.forename: John M
authors.initials: JM
authors.lastname: Redden
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kapiloff
authors.forename: Kimberly L
authors.initials: KL
authors.lastname: Dodge-Kafka
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism* / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D009206:Myocardium / Q000378:metabolism; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors*; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C526078:Akap7 protein, rat; D002352:Carrier Proteins; D020033:Protein Isoforms; D011506:Proteins; C073882:phosphoprotein phosphatase inhibitor 1; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D054645:Protein Phosphatase 1