The Phosphatase PHLPP Controls the Cellular Levels of Protein Kinase C

The life cycle of protein kinase C (PKC) is controlled by multiple phosphorylation and dephosphorylation steps. The maturation of PKC requires three ordered phosphorylations, one at the activation loop and two at COOH-terminal sites, the turn motif and the hydrophobic motif, to yield a stable and signaling-competent enzyme. Dephosphorylation of the enzyme leads to protein degradation. We have recently discovered a novel family of protein phosphatases named PH domain leucine-rich repeat protein phosphatase (PHLPP) whose members terminate Akt signaling by dephosphorylating the hydrophobic motif on Akt. Here we show that the two PHLPP isoforms, PHLPP1 and PHLPP2, also dephosphorylate the hydrophobic motif on PKC βII, an event that shunts PKC to the detergent-insoluble fraction, effectively terminating its life cycle. Deletion mutagenesis reveals that the PH domain is necessary for the effective dephosphorylation of PKC βII by PHLPP in cells, whereas the PDZ-binding motif, required for Akt regulation, is dispensable. The phorbol ester-mediated dephosphorylation of the hydrophobic site, but not the turn motif or activation loop, is insensitive to okadaic acid, consistent with PHLPP, a PP2C family member, controlling the hydrophobic site. In addition, knockdown of PHLPP expression reduces the rate of phorbol ester-triggered dephosphorylation of the hydrophobic motif, but not turn motif, of PKC α. Last, we show that depletion of PHLPP in colon cancer and normal breast epithelial cells results in an increase in conventional and novel PKC levels. These data reveal that PHLPP controls the cellular levels of PKC by specifically dephosphorylating the hydrophobic motif, thus destabilizing the enzyme and promoting its degradation. The life cycle of protein kinase C (PKC) is controlled by multiple phosphorylation and dephosphorylation steps. The maturation of PKC requires three ordered phosphorylations, one at the activation loop and two at COOH-terminal sites, the turn motif and the hydrophobic motif, to yield a stable and signaling-competent enzyme. Dephosphorylation of the enzyme leads to protein degradation. We have recently discovered a novel family of protein phosphatases named PH domain leucine-rich repeat protein phosphatase (PHLPP) whose members terminate Akt signaling by dephosphorylating the hydrophobic motif on Akt. Here we show that the two PHLPP isoforms, PHLPP1 and PHLPP2, also dephosphorylate the hydrophobic motif on PKC βII, an event that shunts PKC to the detergent-insoluble fraction, effectively terminating its life cycle. Deletion mutagenesis reveals that the PH domain is necessary for the effective dephosphorylation of PKC βII by PHLPP in cells, whereas the PDZ-binding motif, required for Akt regulation, is dispensable. The phorbol ester-mediated dephosphorylation of the hydrophobic site, but not the turn motif or activation loop, is insensitive to okadaic acid, consistent with PHLPP, a PP2C family member, controlling the hydrophobic site. In addition, knockdown of PHLPP expression reduces the rate of phorbol ester-triggered dephosphorylation of the hydrophobic motif, but not turn motif, of PKC α. Last, we show that depletion of PHLPP in colon cancer and normal breast epithelial cells results in an increase in conventional and novel PKC levels. These data reveal that PHLPP controls the cellular levels of PKC by specifically dephosphorylating the hydrophobic motif, thus destabilizing the enzyme and promoting its degradation. Protein phosphorylation defines one of the most important and pervasive regulatory mechanisms in cell signaling. Crucial cellular decisions such as those between death or survival and proliferation or differentiation are made depending on the phosphorylation state of signaling molecules. Thus, precise control of the balance between phosphorylation and dephosphorylation is critical for living organisms to maintain normal physiological functions. Dysregulation of signaling pathways that results in disturbing this balance leads to the development of diseases such as cancer and diabetes. Loss of control of either phosphorylation or dephosphorylation mechanisms leads to pathogenic states, and both kinases and phosphatases have been identified as oncogenes or tumor suppressors (1Hanahan D. Weinberg R.A. Cell. 2000; 100: 57-70Abstract Full Text Full Text PDF PubMed Scopus (22275) Google Scholar). We have recently identified a novel family of Ser/Thr phosphatases, which we named PH domain leucine-rich repeat protein phosphatase (PHLPP) 3The abbreviations used are:PHLPPPH domain leucine-rich repeat protein phosphataseGSTglutathione S-transferasePDBuphorbol 12,13-dibutyratePDK-1phosphoinositide-dependent kinase 1PKCprotein kinase CPMAphorbol 12-myristate 13-acetatesiRNAsmall interfering RNAHAhemagglutininmAbmonoclonal antibodyPHpleckstrin homologyLRRleucine rich repeatOAokadaic acidWTwild type.3The abbreviations used are:PHLPPPH domain leucine-rich repeat protein phosphataseGSTglutathione S-transferasePDBuphorbol 12,13-dibutyratePDK-1phosphoinositide-dependent kinase 1PKCprotein kinase CPMAphorbol 12-myristate 13-acetatesiRNAsmall interfering RNAHAhemagglutininmAbmonoclonal antibodyPHpleckstrin homologyLRRleucine rich repeatOAokadaic acidWTwild type. based on domain composition (2Gao T. Furnari F. Newton A.C. Mol. Cell. 2005; 18: 13-24Abstract Full Text Full Text PDF PubMed Scopus (714) Google Scholar, 3Brognard J. Sierecki E. Gao T. Newton A.C. Mol. Cell. 2007; 25: 917-931Abstract Full Text Full Text PDF PubMed Scopus (458) Google Scholar). PHLPP comprises three isozymes: the alternatively and which in an on and PHLPP1 and at the PHLPP1 and a phosphatase domain and dephosphorylate Akt in in a (2Gao T. Furnari F. Newton A.C. Mol. Cell. 2005; 18: 13-24Abstract Full Text Full Text PDF PubMed Scopus (714) Google Scholar, 3Brognard J. Sierecki E. Gao T. Newton A.C. Mol. Cell. 2007; 25: 917-931Abstract Full Text Full Text PDF PubMed Scopus (458) Google Scholar). both PHLPP specifically dephosphorylate the hydrophobic motif of Akt in and the enzyme in cells, terminate Akt signaling by Akt J. Sierecki E. Gao T. Newton A.C. Mol. Cell. 2007; 25: 917-931Abstract Full Text Full Text PDF PubMed Scopus (458) Google Scholar). the of Akt signaling on the of a the PDZ-binding motif, at the of the in the phosphorylation mechanisms of Akt and PKC A.C. J. PubMed Scopus Google of the hydrophobic phosphorylation motif, PHLPP is a to PKC family PH domain leucine-rich repeat protein phosphatase phorbol kinase protein kinase C phorbol 12-myristate interfering rich repeat okadaic type. PH domain leucine-rich repeat protein phosphatase phorbol kinase protein kinase C phorbol 12-myristate interfering rich repeat okadaic type. Akt and PKC are by phosphorylation at two the kinase family A.C. J. PubMed Scopus Google Scholar). a at the to the the activation loop D. F. J. PubMed Scopus Google Scholar, J. Full Text Full Text PDF PubMed Scopus Google Scholar). The phosphorylation by the phosphorylation of a at the to as the hydrophobic phosphorylation motif and to in and in PKC conventional PKC the of phosphorylation of the hydrophobic is by A.C. J. Full Text PDF PubMed Google Scholar, Newton A.C. Full Text Full Text PDF PubMed Scopus Google Scholar). The of Akt and PKC a site, the turn motif, whose phosphorylation is required for phosphorylation on the hydrophobic motif of A.C. J. PubMed Scopus Google Scholar, A.C. PubMed Scopus Google Scholar, F. J. Full Text Full Text PDF PubMed Scopus Google Scholar). The two phosphorylation loop and are of the hydrophobic both Akt and but at this in the of two phosphorylation the of the enzyme. Akt at the of the of enzyme at both the and the hydrophobic site, D. J. Full Text Full Text PDF PubMed Scopus Google Scholar). Thus, dephosphorylation of results in effective phosphorylation at the hydrophobic controls the of the enzyme A.C. PubMed Scopus Google Scholar, PubMed Google Scholar). that the dephosphorylation of this the of The phosphorylation of conventional is to PKC a The enzyme is of which PKC to the thus an the PKC an in which the enzyme is to one of activation of of cells with tumor promoting phorbol dephosphorylation and of the with the detergent-insoluble of cells, to J. PubMed Scopus Google Scholar, F. J. PubMed Scopus Google Scholar). that dephosphorylation is not required for a recently been in which PKC is and J. Full Text Full Text PDF PubMed Scopus Google Scholar). PKC is the of the and of PKC signaling is controlled by the dephosphorylation F. J. PubMed Scopus Google Scholar, J. PubMed Scopus Google Scholar). is the phosphatases for dephosphorylating been that and dephosphorylate PKC and βII in J. PubMed Scopus Google Scholar, Newton A.C. Full Text Full Text PDF PubMed Scopus Google Scholar). of with PKC in the of phorbol cells F. J. Full Text Full Text PDF PubMed Scopus Google Scholar). In addition, of cells with okadaic acid, an of and phosphatases, phorbol dephosphorylation of PKC F. J. Full Text Full Text PDF PubMed Scopus Google Scholar). the of PHLPP in dephosphorylating conventional We show that of either PHLPP1 or in cells results in of PKC βII in the detergent-insoluble of depletion of PHLPP1 or the phorbol dephosphorylation of PKC specifically at the hydrophobic motif site. knockdown of both PHLPP in cancer and normal cells results in an increase in PKC Thus, PHLPP specifically the hydrophobic motif of effectively terminating the of and acid, and and The PKC and PKC βII a PKC for and of PKC βII an an and PHLPP1 and for of PKC βII that specifically the activation loop of PKC and Newton A.C. Full Text Full Text PDF PubMed Scopus Google Scholar). that the and are for the turn motif and hydrophobic motif, of PKC and not with at the of of PHLPP1 and been (2Gao T. Furnari F. Newton A.C. Mol. Cell. 2005; 18: 13-24Abstract Full Text Full Text PDF PubMed Scopus (714) Google Scholar, 3Brognard J. Sierecki E. Gao T. Newton A.C. Mol. Cell. 2007; 25: 917-931Abstract Full Text Full Text PDF PubMed Scopus (458) Google Scholar). are two of the PHLPP1 which we named and J. Sierecki E. Gao T. Newton A.C. Mol. Cell. 2007; 25: 917-931Abstract Full Text Full Text PDF PubMed Scopus (458) Google Scholar). The PHLPP1 used in this is The expression of PHLPP1 a PH domain of PHLPP1 a domain of PHLPP1 and as (2Gao T. Furnari F. Newton A.C. Mol. Cell. 2005; 18: 13-24Abstract Full Text Full Text PDF PubMed Scopus (714) Google Scholar, 3Brognard J. Sierecki E. Gao T. Newton A.C. Mol. Cell. 2007; 25: 917-931Abstract Full Text Full Text PDF PubMed Scopus (458) Google Scholar). The of PHLPP1 as or in the PH domain PP2C domain and the and the and on (2Gao T. Furnari F. Newton A.C. Mol. Cell. 2005; 18: 13-24Abstract Full Text Full Text PDF PubMed Scopus (714) Google or and on T. Newton A.C. J. Full Text Full Text PDF PubMed Scopus Google Scholar). expression of the PH domain of PHLPP1 not in cells, the PH domain as a protein for the The expression of of PKC βII the and as T. Newton A.C. J. Full Text Full Text PDF PubMed Scopus Google Scholar, D. E. Newton A.C. J. Full Text Full Text PDF PubMed Scopus Google Scholar). The by as The of and and on In protein of and as (2Gao T. Furnari F. Newton A.C. Mol. Cell. 2005; 18: 13-24Abstract Full Text Full Text PDF PubMed Scopus (714) Google Scholar). PKC βII and cells in and with βII for The cells in and and βII The dephosphorylation in a and at for The of βII and in the and and and cells in and at in of cell used for of The for PHLPP is of and the are as the for and for PHLPP2, and The of the used in between and that the PHLPP1 are the in both and thus are effective at PHLPP1 the of cells in The cells by and the cell to at for at The is to as the The the is to as the of PKC βII or as (2Gao T. Furnari F. Newton A.C. Mol. Cell. 2005; 18: 13-24Abstract Full Text Full Text PDF PubMed Scopus (714) Google Scholar). the cells in and the cell to the PKC βII as or the to The in and in by and Protein the between the of PKC βII and cells with with PKC βII or The cells in and the cell with at for in and in and by and Dephosphorylation and of dephosphorylation and of or cells with or for as in the cells in and the of and PKC by to a the is the of and is is the on the is the of that and is the rate PHLPP1 PKC βII in and in have that the PP2C domain of PHLPP1 Akt in (2Gao T. Furnari F. Newton A.C. Mol. Cell. 2005; 18: 13-24Abstract Full Text Full Text PDF PubMed Scopus (714) Google Scholar). we the PP2C domain of of PKC βII in the PP2C domain of PHLPP1 as a protein and (2Gao T. Furnari F. Newton A.C. Mol. Cell. 2005; 18: 13-24Abstract Full Text Full Text PDF PubMed Scopus (714) Google Scholar). PKC βII this PKC is at this PKC is at the two sites, and and at the activation loop site, Newton A.C. Full Text Full Text PDF PubMed Scopus Google Scholar). The in that the PP2C domain effectively the hydrophobic motif site, and the turn motif, In the activation loop to dephosphorylation by the PP2C domain of PHLPP1 in These results reveal that the PP2C domain of PHLPP1 the hydrophobic motif and the turn motif of PKC in PHLPP1 PKC in we or with PKC βII in cells and the of PKC The in show the of PKC βII in the and detergent-insoluble of the of the PKC βII in control cells in the and as an to the that is at the two COOH-terminal of and at the Newton A.C. J. Full Text PDF PubMed Google Scholar). In of PHLPP1 in the of a of PKC βII to PKC in the in the detergent-insoluble that the dephosphorylation of the turn motif and hydrophobic motif are Thus, of of at one COOH-terminal site, are not These results reveal that of PHLPP1 with PKC βII in cells the dephosphorylation and of PKC in the detergent-insoluble of the of at the turn motif or the hydrophobic motif in the of PKC to the detergent-insoluble we two of PKC and that the not by on but on data in These data that of on but not shunts PKC to the detergent-insoluble PHLPP1 with PKC phosphatases are to with as mechanisms to J. PubMed Google Scholar). PHLPP1 with PKC βII in cells, we cells PKC βII and PKC βII with either a or an expression of that PKC βII in the of levels of PKC βII in the of or that the in the of PKC in the of the detergent-insoluble of PKC in cells but not or not reveal that PKC βII specifically with and not of the PP2C family of phosphatases, in the in PKC βII that the to cells of PKC βII and The data in show that PHLPP1 to the domain as as the kinase domain not a of the the the domain or the Thus, the domain and kinase the that the of PKC to We which in PHLPP1 the to PKC The leucine-rich repeat the PP2C and the of PHLPP1 as and the PH domain of PHLPP1 as a PKC βII with or to or PKC βII with and of PHLPP1 and as as the the domain at levels or the PH the of PKC with three that the PP2C domain the the with PKC and that this is in the of the In addition, to the PH domain the of PHLPP1 with The PH of PHLPP1 for Dephosphorylation of PKC the of regulatory in we the of either the PH domain or PDZ-binding motif on the of PHLPP1 to the of PKC in the detergent-insoluble of in and of PHLPP1 with PKC βII in the of a of PKC βII in the detergent-insoluble of the cells that in cells but of PKC in the detergent-insoluble in cells with a of PHLPP1 in the COOH-terminal PDZ-binding motif and In of the PH domain the of PHLPP1 to dephosphorylate PKC βII and the to the detergent-insoluble Thus, the PH domain is necessary for dephosphorylation of PKC by PHLPP in We of the PH domain or the PDZ-binding motif in PHLPP1 its with PKC that of the PH domain in a of the of PKC βII to PHLPP1 and is consistent with the PH domain of PHLPP1 a for PKC βII as in In of the PDZ-binding motif on the of PHLPP1 with PKC βII and These data reveal that the PH and not the PDZ-binding motif, controls the of PHLPP1 with The of the PHLPP PHLPP2, PKC are two in the PHLPP we the PHLPP2, also that of the of PKC βII in the detergent-insoluble of the cells that PKC βII specifically with in cells results that to PHLPP1 in dephosphorylating PKC βII in Dephosphorylation of the of PKC to the of PHLPP in the phorbol dephosphorylation of we the phosphorylation in the of PKC PKC is the conventional PKC in cells, we the of PHLPP knockdown on this to PKC βII, PKC is by PHLPP in cells not cells with for or and the cell for the dephosphorylation of PKC α. that the of the by the for both the hydrophobic motif and turn motif and of at both PKC is the and in cells, novel also to this In addition, the of with the the dephosphorylation of PKC that phorbol have been to the maturation of PKC J. Full Text Full Text PDF PubMed Scopus Google Scholar, D. PubMed Scopus Google that the in is PKC that been not the of dephosphorylation of the activation loop in PKC not not and as that an by the for but not that dephosphorylation of that of is consistent with that a of PKC at but not in cells Newton A.C. Full Text Full Text PDF PubMed Scopus Google Scholar). These data that the phosphatase for dephosphorylating the hydrophobic motif of PKC the of PKC signaling. The data that PHLPP is the phosphatase controlling the phosphorylation state of hydrophobic motif of PP2C family members are not by okadaic J. Full Text PDF PubMed Google to dephosphorylation of PKC is to We the phosphorylation state at of the three phosphorylation on PKC βII in cells with or phorbol and with or have that phosphorylation at the activation loop is required for of phosphorylation at this PKC is and of the of signaling-competent PKC is at this in cells Newton A.C. Full Text Full Text PDF PubMed Scopus Google Scholar). with and the the data three show that cells with in an increase in the phosphorylation at for both and the of PKC βII with control cells and to a in cells with to not dephosphorylation at the of this and These results are consistent with the dephosphorylation of the activation loop of PKC by an the of PKC βII is at both COOH-terminal Newton A.C. Full Text Full Text PDF PubMed Scopus Google the phosphorylation of both the and in PKC βII not by and and and the of on sites, we two we of the of the with at this to dephosphorylation in the of protein that is not at the in cells F. J. Full Text Full Text PDF PubMed Scopus Google Scholar, Newton A.C. J. Full Text Full Text PDF PubMed Scopus Google Scholar). Thus, is not at the turn motif, the used to the of the site. that the phosphorylation state of in the with cells and a we the of on dephosphorylation of the turn and hydrophobic of the of the turn motif and of the hydrophobic motif to and the dephosphorylation of the turn motif by and but on the dephosphorylation of the hydrophobic motif and The dephosphorylation of in the by and These data that the dephosphorylation of but not is controlled by an of the phosphorylation state of to is consistent with PHLPP the protein phosphatase for the hydrophobic of PHLPP Dephosphorylation of PKC the of PHLPP in phorbol dephosphorylation of PKC in cells, specifically PHLPP1 or used to cells of We used cells for the we have that PHLPP1 effectively in this cell (2Gao T. Furnari F. Newton A.C. Mol. Cell. 2005; 18: 13-24Abstract Full Text Full Text PDF PubMed Scopus (714) Google Scholar). to with cells, we the dephosphorylation of PKC in cells is the PKC The two in show that the expression of both PHLPP1 and effectively in cells with cells with for not dephosphorylation of the activation loop of PKC in the or cells the of the turn motif the of dephosphorylation of PKC at this not in the or cells In the in an of hydrophobic motif phosphorylation of PKC in the control cells and and either PHLPP1 or or both this dephosphorylation and depletion of either of PHLPP to dephosphorylation of the hydrophobic motif and to maintain PKC in a Thus, depletion of both PHLPP In addition, of PKC protein in the of consistent with the that dephosphorylation protein of PKC a the of PKC a phorbol PKC not by These data reveal that both PHLPP1 and the dephosphorylation of PKC in and this dephosphorylation is for the hydrophobic motif of the of dephosphorylation in the of PKC the of PKC in PHLPP knockdown used to cells is in of cells with control or both PHLPP1 and with for that phorbol in the dephosphorylation of PKC and an in the of the data three to a that the for the dephosphorylation at both and as as the of PKC the and depletion of PHLPP1 and on the of at the for dephosphorylation of this for the PHLPP knockdown with for the dephosphorylation of in cells of PHLPP with control the data to an that as PKC on in cells PHLPP with control of the PKC in cells of PHLPP with in control cells The of an with in PHLPP knockdown cells the of PKC at and not not by the with PHLPP knockdown a of PKC to the of PKC to in the knockdown cells with in control that the PKC that the in of PKC to of PKC to dephosphorylation on for in the to PHLPP dephosphorylation of the Thus, a of PKC to dephosphorylation at but not in cells of PHLPP The expression of a phorbol PKC PKC not by in either control or PHLPP knockdown results that both PHLPP the dephosphorylation of PKC on the hydrophobic motif also show that this dephosphorylation is required for one of phorbol ester-mediated of of PKC by PHLPP levels are in a of colon Google Scholar, J. PubMed Scopus Google Scholar). PHLPP levels control PKC levels in colon cancer cell we specifically PHLPP2, or both PHLPP a colon cancer cell that PHLPP the cell reveals that depletion of either or a increase in the levels of PKC PKC levels not by PHLPP PKC levels knockdown a increase in PKC an increase that both PHLPP1 and These data reveal PHLPP controls the levels of PKC βII in the colon cancer cell the expression of PKC in normal cells is by PHLPP, we two normal breast epithelial cell with control or and the expression of The expression of both PHLPP effectively by the of in those cells PHLPP1 and knockdown of PHLPP1 and a increase in the levels of PKC PKC βII, and the novel PKC with the control cells PKC PKC βII, and PKC These results that PHLPP is in the of conventional and novel PKC in normal cells, consistent with the that dephosphorylation controls the of The phosphorylation state of PKC controls its as by the that the enzyme is in cells the 2000; PubMed Scopus Google Scholar). the phosphorylation of PKC is dephosphorylation mechanisms are to a in controlling the of PKC and thus the of the PKC we identified the novel protein phosphatases PHLPP1 and as in the dephosphorylation of PKC in We that both phosphatases and dephosphorylate PKC βII on the hydrophobic motif, an event that shunts PKC βII to the detergent-insoluble of cells In addition, depletion of PHLPP1 or phorbol dephosphorylation of the hydrophobic motif on PKC that both PHLPP are of PKC signaling. a of PHLPP in normal knockdown of PHLPP in a colon cancer cell with PHLPP expression a increase in the expression of PKC βII, an whose levels are in colon cancer Google Scholar). In addition, knockdown of PHLPP in normal breast epithelial cells results in a increase of PKC Thus, PHLPP control the of cellular PKC by dephosphorylating a site, the hydrophobic motif, that controls the of this family of PHLPP the of of PHLPP for the hydrophobic motif of PKC is consistent with that PHLPP1 and the dephosphorylation of the hydrophobic motif on a Akt (2Gao T. Furnari F. Newton A.C. Mol. Cell. 2005; 18: 13-24Abstract Full Text Full Text PDF PubMed Scopus (714) Google Scholar). have that a phosphatase with PKC in the of cells F. J. Full Text Full Text PDF PubMed Scopus Google Scholar). results that the phosphorylation state of the activation loop and turn motif are controlled by a phosphatase dephosphorylation of both is to okadaic In results depletion and that the hydrophobic motif is by PHLPP isoforms, consistent with the that the phosphorylation state of the hydrophobic motif is not to okadaic acid, an that not PP2C family is that PHLPP not between the turn motif and hydrophobic motif in but the hydrophobic motif in These data the of cellular in In to conventional the PKC family the novel and the of and have a of Ser/Thr at the of the hydrophobic Thus, this in the a of with we show that the expression of PKC not by depletion of PHLPP cells, whereas expression of PKC and in the knockdown These data that PHLPP controls the levels of conventional and but not PKC have physiological in cellular 2007; PubMed Scopus Google the of of PKC is cell The data and knockdown show that both members of the PHLPP PHLPP1 and PHLPP2, dephosphorylate conventional in both PHLPP Akt (2Gao T. Furnari F. Newton A.C. Mol. Cell. 2005; 18: 13-24Abstract Full Text Full Text PDF PubMed Scopus (714) Google Scholar, 3Brognard J. Sierecki E. Gao T. Newton A.C. Mol. Cell. 2007; 25: 917-931Abstract Full Text Full Text PDF PubMed Scopus (458) Google Scholar). PHLPP1 and of Akt and signaling pathways of Akt J. Sierecki E. Gao T. Newton A.C. Mol. Cell. 2007; 25: 917-931Abstract Full Text Full Text PDF PubMed Scopus (458) Google Scholar). to PHLPP of signaling of PHLPP in of of PHLPP in either the PH domain or PDZ-binding motif reveal that regulatory in We have that the PDZ-binding motif of PHLPP1 is necessary for the of PHLPP1 of the three COOH-terminal the the of PHLPP1 to dephosphorylate and In of the PH domain in phosphatase Akt in cells (2Gao T. Furnari F. Newton A.C. Mol. Cell. 2005; 18: 13-24Abstract Full Text Full Text PDF PubMed Scopus (714) Google Scholar). In the data in this that the PH domain of PHLPP1 is required for its to dephosphorylate PKC in cells, whereas the PDZ-binding motif is for this of the the phosphatase of PHLPP1 PKC in These data reveal that the regulatory of PHLPP in the of the phosphatase and that of PHLPP is critical for in its signaling. on the phosphatase in to the or by for the with of the regulatory that Akt PDZ-binding dephosphorylation of whereas of the regulatory that PKC PH Akt dephosphorylation in Thus, for of the PHLPP a with the of PHLPP to The of PKC and Akt by the PH domain and PDZ-binding motif, an for PHLPP to specifically dephosphorylate two family with the PDZ-binding motif in PHLPP the PH domain in and is in PHLPP that the of PHLPP in organisms to Akt signaling and that the of as regulatory to the PHLPP Dephosphorylation of the this we used phorbol dephosphorylation of conventional as a to the dephosphorylation of conventional PKC is not an to phorbol been that dephosphorylation and of PKC in cells of the D. J. Full Text PDF PubMed Google or cells F. J. PubMed Scopus Google Scholar). Thus, dephosphorylation of PKC is to a PKC for degradation. the of and are a of PKC dephosphorylation at a The of PKC is with such as those phorbol or the J. J. PubMed Google Scholar). have been to PKC by and mechanisms J. Full Text Full Text PDF PubMed Scopus Google Scholar). data a in which PHLPP the in the we show that dephosphorylation of that of we show that depletion of PHLPP results in the of a of PKC that is on but not which is to degradation. the of of the PKC by the also reveal that the to PKC to the detergent-insoluble is of at PHLPP the of of PKC expression been to and tumor Google Scholar, J. PubMed Scopus Google Scholar, J. Full Text PDF PubMed Google Scholar). the for the expression of PKC in In this we that the of conventional and novel PKC by the expression of PHLPP1 and PHLPP2, consistent with the of PHLPP in PKC by dephosphorylating PKC and promoting its We have that the PHLPP levels in of colon cancer cell not the expression levels of cells with PHLPP have phosphorylation of the hydrophobic motif on Akt (2Gao T. Furnari F. Newton A.C. Mol. Cell. 2005; 18: 13-24Abstract Full Text Full Text PDF PubMed Scopus (714) Google Scholar). the of PHLPP dephosphorylation of the hydrophobic motif on PKC and for PKC controls the and thus levels of the for Akt controls the of hydrophobic motif and with a of PHLPP in controlling the levels of cellular the of PKC expression in normal breast epithelial cells is by the expression of PHLPP The levels of PKC and PKC βII in that this increase of PKC expression PHLPP in normal cell not or to PKC in cancer cell and is that the PHLPP and PKC in the normal cells is in the cancer cells, mechanisms to cell thus in control of PKC by the of PHLPP knockdown on Akt phosphorylation are at an of in normal cells such as the with cells such as J. Sierecki E. Gao T. Newton A.C. Mol. Cell. 2007; 25: 917-931Abstract Full Text Full Text PDF PubMed Scopus (458) Google Scholar). We in that depletion of PHLPP the colon cancer a increase in PKC βII protein is PKC βII protein levels are in colon cancer Google Scholar). the for the PKC βII in colon cancer is by levels of PHLPP to on the between PHLPP and PKC in are of in novel in cancer We for with of the