PT  - JOURNAL ARTICLE
AU  - Arptia Singh
AU  - John M Redden
AU  - Michael Kapiloff
AU  - Kimberly Dodge-Kafka
TI  - The large isoforms of AKAP18 mediate the phosphorylation of Inhibitor-1 by PKA and the inhibition of PP1 activity
AID  - 10.1124/mol.110.065425
DP  - 2010 Dec 13
TA  - Molecular Pharmacology
PG  - mol.110.065425
4099  - http://molpharm.aspetjournals.org/content/early/2010/12/13/mol.110.065425.short
4100  - http://molpharm.aspetjournals.org/content/early/2010/12/13/mol.110.065425.full
AB  - Inhibitor-1 (I-1) is phosphorylated on threonine residue 35 (Thr-35) 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, 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. Importantly, 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 upon PKA binding to the scaffold. These observations reveal an additional level of complexity in PP1 regulation due to its association with AKAP18 multi-molecular signaling complexes, and suggest that targeting of AKAP18 complexes may be an alternative method to alter phosphatase activity and modulate specific substrate dephosphorylation.