PHLPP and a Second Isoform, PHLPP2, Differentially Attenuate the Amplitude of Akt Signaling by Regulating Distinct Akt Isoforms

Brognard, John; Sierecki, Emma; Gao, Tianyan; Newton, Alexandra C.

doi:10.1016/j.molcel.2007.02.017

Cited by 529 publications

(673 citation statements)

References 42 publications

Supporting

Mentioning

638

Contrasting

Unclassified

Order By: Relevance

“…20,[122][123][124][125][126] PHLPP (PH domain leucine-rich repeat protein phosphatase) is a protein phosphatase 2C family member which has been discovered to dephosphorylate and inhibit Akt. [126][127][128][129][130] Expression of PHLPP is repressed in cancer cells resulting in elevated Akt activation. 128,130 Interestingly, our study using PHLPP1 knockout (KO) mice suggest that PHLPP1, in addition to cytosol, localizes at mitochondria and negatively regulates mitochondrial Akt activity, decreasing mitoHK-II.…”

Section: Akt and Mitochondrial Hk-ii In Protectionmentioning

confidence: 99%

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

2014

View full text Add to dashboard Cite

Accumulating evidence reveals that metabolic and cell survival pathways are closely related, sharing common signaling molecules. Hexokinase catalyzes the phosphorylation of glucose, the rate-limiting first step of glycolysis. Hexokinase II (HK-II) is a predominant isoform in insulin-sensitive tissues such as heart, skeletal muscle, and adipose tissues. It is also upregulated in many types of tumors associated with enhanced aerobic glycolysis in tumor cells, the Warburg effect. In addition to the fundamental role in glycolysis, HK-II is increasingly recognized as a component of a survival signaling nexus. This review summarizes recent advances in understanding the protective role of HK-II, controlling cellular growth, preventing mitochondrial death pathway and enhancing autophagy, with a particular focus on the interaction between HK-II and Akt/mTOR pathway to integrate metabolic status with the control of cell survival.

show abstract

Section: Akt and Mitochondrial Hk-ii In Protectionmentioning

confidence: 99%

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

2014

View full text Add to dashboard Cite

show abstract

“…The recent discovery of two phosphatases, PHLPP1 and PHLPP2 [33], which terminate Akt signalling by dephosphorylating Ser 473 in an isoform-specific manner, prompted us to evaluate their levels in skeletal muscle biopsies from control and type 2 diabetic patients (Fig. 8).…”

Section: Resultsmentioning

confidence: 99%

“…An alternative mechanism could be the implication of isoform specific phosphatases. Indeed, PHLPP1 dephosphorylates the Ser 473 residue of Akt2, whereas Akt1-Ser 473 is specifically dephosphorylated by PHLPP2 [33]. Therefore we measured PHLPP1 and PHLPP2 mRNA expression in skeletal muscle biopsies.…”

Section: Discussionmentioning

confidence: 99%

Isoform-specific defects of insulin stimulation of Akt/protein kinase B (PKB) in skeletal muscle cells from type 2 diabetic patients

et al. 2008

View full text Add to dashboard Cite

show abstract

“…2,3 To date four PHLPP substrates, Akt, PKC, Mst1 and S6K1, have been identified, all kinases involved in cell survival or apoptosis. [4][5][6][7] Dephosphorylation inactivates Akt, S6K1 and PKC, and subsequently cell survival signaling, whereas dephosphorylation of Mst1 activates its apoptotic function.…”

mentioning

confidence: 99%

Transcription factor C/EBP-β induces tumor-suppressor phosphatase PHLPP2 through repression of the miR-17–92 cluster in differentiating AML cells

et al. 2016

View full text Add to dashboard Cite

PHLPP2, a member of the PH-domain leucine-rich repeat protein phosphatase (PHLPP) family, which targets oncogenic kinases, has been actively investigated as a tumor suppressor in solid tumors. Little is known, however, regarding its regulation in hematological malignancies. We observed that PHLPP2 protein expression, but not its mRNA, was suppressed in late differentiation stage acute myeloid leukemia (AML) subtypes. MicroRNAs (miR or miRNAs) from the miR-17-92 cluster, oncomir-1, were shown to inhibit PHLPP2 expression and these miRNAs were highly expressed in AML cells that lacked PHLPP2 protein.Studies showed that miR-17-92 cluster regulation was, surprisingly, independent of transcription factors c-MYC and E2F in these cells; instead all-trans-retinoic acid (ATRA), a drug used for terminally differentiating AML subtypes, markedly suppressed miR-17-92 expression and increased PHLPP2 protein levels and phosphatase activity. Finally, we demonstrate that the effect of ATRA on miR-17-92 expression is mediated through its target, transcription factor C/EBPβ, which interacts with the intronic promoter of the miR-17-92 gene to inhibit transactivation of the cluster. These studies reveal a novel mechanism for upregulation of the phosphatase activity of PHLPP2 through C/EBPβ-mediated repression of the miR-17-92 cluster in terminally differentiating myeloid cells. Phosphatases are pivotal components of intracellular signaling cascades, controlling essential processes like metabolism, apoptosis, proliferation and differentiation. 1 The PH-domain leucine-rich repeat protein phosphatase (PHLPP) family serine-threonine phosphatases are emerging as central factors in cell survival and death regulation. The PHLPP2 is a member of this family. 2,3 To date four PHLPP substrates, Akt, PKC, Mst1 and S6K1, have been identified, all kinases involved in cell survival or apoptosis. 4-7 Dephosphorylation inactivates Akt, S6K1 and PKC, and subsequently cell survival signaling, whereas dephosphorylation of Mst1 activates its apoptotic function.PHLPP protein expression and activity is suppressed through various mechanisms in cancers. Although most studies on PHLPP2 have focused on genetic alterations in solid tumors, 8 PHLPP2 protein expression in small cell lung and colorectal cancers is also restricted through translational suppression 9 and post-transcriptional control by microRNAs (miR or miRNAs), miR-205 and miR-224. 10,11 The PHLPP2 3' untranslated region (3'UTR) harbors complementary binding sites for a subset of miRNAs belonging to the miRNA-17-92 cluster. 12 This cluster comprises six miRNAs on chromosome 13, transcribed as a single polycistronic unit. 13,14 Also known as oncomir-1, the cluster enhances cell proliferation or inhibits apoptosis by suppressing targets such as Bim, E2F1 and PTEN and is markedly overexpressed in human cancers. [15][16][17][18][19][20][21] Reduced levels of PHLPP2 in chemoresistant miR-17-92 overexpressing mantle cell lymphomas had suggested that the phosphatase could be a target of oncomir-1. 12 Kno...

show abstract

PHLPP and a Second Isoform, PHLPP2, Differentially Attenuate the Amplitude of Akt Signaling by Regulating Distinct Akt Isoforms

Cited by 529 publications

References 42 publications

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy

Isoform-specific defects of insulin stimulation of Akt/protein kinase B (PKB) in skeletal muscle cells from type 2 diabetic patients

Transcription factor C/EBP-β induces tumor-suppressor phosphatase PHLPP2 through repression of the miR-17–92 cluster in differentiating AML cells

Contact Info

Product

Resources

About