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http://purl.uniprot.org/citations/20576936http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/20576936http://www.w3.org/2000/01/rdf-schema#comment"

Rationale

The recently discovered PHLPP-1 (PH domain leucine-rich repeat protein phosphatase-1) selectively dephosphorylates Akt at Ser473 and terminates Akt signaling in cancer cells. The regulatory role of PHLPP-1 in the heart has not been considered.

Objective

To test the hypothesis that blockade/inhibition of PHLPP-1 could constitute a novel way to enhance Akt signals and provide cardioprotection.

Methods and results

PHLPP-1 is expressed in neonatal rat ventricular myocytes (NRVMs) and in adult mouse ventricular myocytes (AMVMs). PHLPP-1 knockdown by small interfering RNA significantly enhances phosphorylation of Akt (p-Akt) at Ser473, but not at Thr308, in NRVMs stimulated with leukemia inhibitory factor (LIF). The increased phosphorylation is accompanied by greater Akt catalytic activity. PHLPP-1 knockdown enhances LIF-mediated cardioprotection against doxorubicin and also protects cardiomyocytes against H(2)O(2). Direct Akt effects at mitochondria have been implicated in cardioprotection and mitochondria/cytosol fractionation revealed a significant enrichment of PHLPP-1 at mitochondria. The ability of PHLPP-1 knockdown to potentiate LIF-mediated increases in p-Akt at mitochondria and an accompanying increase in mitochondrial hexokinase-II was demonstrated. We generated PHLPP-1 knockout (KO) mice and demonstrate that AMVMs isolated from KO mice show potentiated p-Akt at Ser473 in response to agonists. When isolated perfused hearts are subjected to ischemia/reperfusion, p-Akt in whole-heart homogenates and in the mitochondrial fraction is significantly increased. Additionally in PHLPP-1 KO hearts, the increase in p-Akt elicited by ischemia/reperfusion is potentiated and, concomitantly, infarct size is significantly reduced.

Conclusions

These results implicate PHLPP-1 as an endogenous negative regulator of Akt activity and cell survival in the heart."xsd:string
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http://purl.uniprot.org/citations/20576936http://purl.uniprot.org/core/author"Huang K."xsd:string
http://purl.uniprot.org/citations/20576936http://purl.uniprot.org/core/author"Smith J.M."xsd:string
http://purl.uniprot.org/citations/20576936http://purl.uniprot.org/core/author"Gao T."xsd:string
http://purl.uniprot.org/citations/20576936http://purl.uniprot.org/core/author"Miyamoto S."xsd:string
http://purl.uniprot.org/citations/20576936http://purl.uniprot.org/core/author"Brown J.H."xsd:string
http://purl.uniprot.org/citations/20576936http://purl.uniprot.org/core/author"Newton A.C."xsd:string
http://purl.uniprot.org/citations/20576936http://purl.uniprot.org/core/author"Castillo R."xsd:string
http://purl.uniprot.org/citations/20576936http://purl.uniprot.org/core/author"Glembotski C.C."xsd:string
http://purl.uniprot.org/citations/20576936http://purl.uniprot.org/core/author"Purcell N.H."xsd:string
http://purl.uniprot.org/citations/20576936http://purl.uniprot.org/core/author"Sussman M.A."xsd:string
http://purl.uniprot.org/citations/20576936http://purl.uniprot.org/core/author"Whittaker R."xsd:string
http://purl.uniprot.org/citations/20576936http://purl.uniprot.org/core/date"2010"xsd:gYear
http://purl.uniprot.org/citations/20576936http://purl.uniprot.org/core/name"Circ Res"xsd:string
http://purl.uniprot.org/citations/20576936http://purl.uniprot.org/core/pages"476-484"xsd:string
http://purl.uniprot.org/citations/20576936http://purl.uniprot.org/core/title"PHLPP-1 negatively regulates Akt activity and survival in the heart."xsd:string
http://purl.uniprot.org/citations/20576936http://purl.uniprot.org/core/volume"107"xsd:string
http://purl.uniprot.org/citations/20576936http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/20576936
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