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

Arpita Singh, John M. Redden, Michael S Kapiloff, Kimberly L. Dodge-Kafka

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)533-540
Number of pages8
JournalMolecular Pharmacology
Volume79
Issue number3
DOIs
StatePublished - Mar 1 2011

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Protein Phosphatase 1
Cyclic AMP-Dependent Protein Kinases
Protein Kinases
Protein Isoforms
Phosphorylation
Threonine
Phosphoric Monoester Hydrolases
Protein Binding
Serine

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

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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. / Singh, Arpita; Redden, John M.; Kapiloff, Michael S; Dodge-Kafka, Kimberly L.

In: Molecular Pharmacology, Vol. 79, No. 3, 01.03.2011, p. 533-540.

Research output: Contribution to journalArticle

Singh, Arpita ; Redden, John M. ; Kapiloff, Michael S ; Dodge-Kafka, Kimberly L. / 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. In: Molecular Pharmacology. 2011 ; Vol. 79, No. 3. pp. 533-540.
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