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 language | English |
|---|---|
| Pages (from-to) | 533-540 |
| Number of pages | 8 |
| Journal | Molecular Pharmacology |
| Volume | 79 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 1 2011 |
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ASJC Scopus subject areas
- Pharmacology
- Molecular Medicine
Cite this
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 journal › Article
}
TY - JOUR
T1 - 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
AU - Singh, Arpita
AU - Redden, John M.
AU - Kapiloff, Michael S
AU - Dodge-Kafka, Kimberly L.
PY - 2011/3/1
Y1 - 2011/3/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=79952000271&partnerID=8YFLogxK
U2 - 10.1124/mol.110.065425
DO - 10.1124/mol.110.065425
M3 - Article
C2 - 21149637
AN - SCOPUS:79952000271
VL - 79
SP - 533
EP - 540
JO - Molecular Pharmacology
JF - Molecular Pharmacology
SN - 0026-895X
IS - 3
ER -