Protein Kinase Cɛ (PKCɛ) and Src Control PKCδ Activation Loop Phosphorylation in Cardiomyocytes

Abstract

Protein kinase Cδ (PKCδ) is unusual among AGC kinases in that it does not require activation loop (Thr505) phosphorylation for catalytic competence. Nevertheless, Thr505 phosphorylation has been implicated as a mechanism that influences PKCδ activity. This study examines the controls of PKCδ-Thr505 phosphorylation in cardiomyocytes. We implicate phosphoinositide-dependent kinase-1 and PKCδ autophosphorylation in the “priming” maturational PKCδ-Thr505 phosphorylation that accompanies de novo enzyme synthesis. In contrast, we show that PKCδ-Thr505 phosphorylation dynamically increases in cardiomyocytes treated with phorbol 12-myristate 13-acetate or the α1-adrenergic receptor agonist norepinephrine via a mechanism that requires novel PKC isoform activity and not phosphoinositide-dependent kinase-1. We used a PKCɛ as novel PKC PKCδ-Thr505 autophosphorylation and PKCδ-Thr505 phosphorylation in show that PKCɛ in PKCδ-Thr505 of PKCɛ as a PKCδ-Thr505 the in PKCδ-Thr505 phosphorylation is PKCδ phosphorylation and implicate in that PKCɛ increases PKCδ-Thr505 phosphorylation in cardiomyocytes and not in and and a in and in PKCδ-Thr505 autophosphorylation is in with a novel PKCδ-Thr505 autophosphorylation mechanism that is PKCɛ and Protein kinase Cδ (PKCδ) is unusual among AGC kinases in that it does not require activation loop (Thr505) phosphorylation for catalytic competence. Nevertheless, Thr505 phosphorylation has been implicated as a mechanism that influences PKCδ activity. This study examines the controls of PKCδ-Thr505 phosphorylation in cardiomyocytes. We implicate phosphoinositide-dependent kinase-1 and PKCδ autophosphorylation in the “priming” maturational PKCδ-Thr505 phosphorylation that accompanies de novo enzyme synthesis. In contrast, we show that PKCδ-Thr505 phosphorylation dynamically increases in cardiomyocytes treated with phorbol 12-myristate 13-acetate or the α1-adrenergic receptor agonist norepinephrine via a mechanism that requires novel PKC isoform activity and not phosphoinositide-dependent kinase-1. We used a PKCɛ as novel PKC PKCδ-Thr505 autophosphorylation and PKCδ-Thr505 phosphorylation in show that PKCɛ in PKCδ-Thr505 of PKCɛ as a PKCδ-Thr505 the in PKCδ-Thr505 phosphorylation is PKCδ phosphorylation and implicate in that PKCɛ increases PKCδ-Thr505 phosphorylation in cardiomyocytes and not in and and a in and in PKCδ-Thr505 autophosphorylation is in with a novel PKCδ-Thr505 autophosphorylation mechanism that is PKCɛ and of PKCδ used kinase phosphoinositide-dependent phorbol 12-myristate kinase novel of used kinase phosphoinositide-dependent phorbol 12-myristate kinase novel of activation in the that PKCδ and a that the the This and phosphorylation of we and that PKCδ is dynamically phosphorylation a in the activation loop (Thr505) require activation loop phosphorylation as a “priming” a In contrast, PKCδ is activation loop activation loop phosphorylation a the of PKCδ controls and of the that PKCδ phosphorylation and in as activation loop phosphorylation has been phosphoinositide-dependent kinase-1 a AGC activation loop the of in phosphorylation PKCδ in that is not the of PKCδ-Thr505 phosphorylation in the the α1-adrenergic receptor agonist norepinephrine and PKCδ-Thr505 phosphorylation via a mechanism that is of PKC and not that PKC that the in PKCδ-Thr505 phosphorylation is isoform and not is a the that PKC activation loop via a the of and as PKCδ-Thr505 kinases in in with the and and the of a a for cardiomyocytes as in of cardiomyocytes is a of for in with and for the the the the as and in and in a with that of or or a Protein and or PKCδ or the In the a for a with in of and with and and and for as the and the in of PKCδ of PKCδ for in the or of kinase in of a and in the or of and with the PKCδ-Thr505 via a and used a the PKCδ-Thr505 phosphorylation mechanism in and cardiomyocytes. that PKCδ a of Thr505 phosphorylation in PKCδ-Thr505 phosphorylation increases dynamically in with or increases in PKCδ-Thr505 phosphorylation PKC isoform not PKC the PKC kinase and phosphorylation require the of that with the the of that does not PKCδ-Thr505 implicate a activity in PKCδ-Thr505 the that PKCδ-Thr505 phosphorylation is we a of the of and PKC as in PKCδ-Thr505 of the of and that as a PKC and as of and activation loop phosphorylation PKCδ and in activation loop phosphorylation as a for is a activation loop phosphorylation for PKC activation loop phosphorylation is a or the and phosphorylation via has not been that increases phosphorylation via a mechanism that is a of does not and phosphorylation is not for and and implicate PKC as the that and PKCδ-Thr505 and phosphorylation via a mechanism that is the and increases in PKCδ-Thr505 and of that the This a of PKC that with and used phosphorylation is not phosphorylation of and PKCδ-Thr505 and and the of PKCδ a and a in or is a kinase with a This a PKCδ-Thr505 autophosphorylation or phosphorylation in de PKCδ that PKCδ-Thr505 phosphorylation is dynamically mechanism is with the that activation loop phosphorylation PKCδ and AGC PKCδ-Thr505 phosphorylation is with activity the of PKCδ-Thr505 phosphorylation in receptor activation and the activation loop of we used activation loop phosphorylation and We that is PKCδ that and in that PKCδ activity is not for activation loop is Thr505 phosphorylation of is is for in that autophosphorylation mechanism Thr505 phosphorylation PKCδ in This phosphorylation a the of the enzyme controls of and Thr505 used and in the or of PKCδ and PKCδ-Thr505 a that activation loop phosphorylation of and that phosphorylation and the of in and that in a in that the activation loop of PKCδ is via a mechanism autophosphorylation and phosphorylation in PKCδ-Thr505 implicate activity PKCδ-Thr505 autophosphorylation or PKCδ-Thr505 phosphorylation in in PKCδ-Thr505 We used PKCɛ and the that PKCɛ as a PKCδ-Thr505 that of increases PKCδ-Thr505 This is not with a in PKCδ is and not PKCδ-Thr505 phosphorylation and not increases PKCδ-Thr505 phosphorylation or PKCδ in cardiomyocytes. used or as a in of treated for with or as with the as that PKCɛ increases PKCδ phosphorylation as a PKCδ-Thr505 and that does not in phosphorylation does not as or phosphorylation of PKCɛ PKCδ via that the in PKCδ-Thr505 phosphorylation is the of enzyme in the we mechanism for isoform of PKCɛ a enzyme as a or kinase and the of PKCδ mechanism for PKCδ-Thr505 we the of and PKCδ in and and that is in the PKCδ the and of and that the of PKCɛ PKCδ-Thr505 phosphorylation a in PKCδ that PKCɛ PKCδ-Thr505 PKCδ-Thr505 is the of PKCδ that the in In contrast, PKCδ-Thr505 is in the and of that for the of PKC in the of PKCδ of in the of that a in PKC increases PKCδ-Thr505 phosphorylation PKCδ PKCδ used or as of and a with or or a with as and as PKCδ as a of the PKCɛ implicate the of PKCɛ as a PKCδ-Thr505 for In PKCδ is a for We that increases PKCδ phosphorylation PKCδ phosphorylation in PKCδ-Thr505 and as a that PKCɛ PKCδ that not increases and PKCδ in PKCδ phosphorylation is with used as as with and require the phosphorylation in increases and phosphorylation in cardiomyocytes. used or as a of treated for with or with the or PKCδ in the or of with as with the as that increases PKCδ phosphorylation via mechanism in cardiomyocytes that the increases in and phosphorylation not a in or activity that activation loop a for the in PKCδ-Thr505 phosphorylation requires PKCδ-Thr505 phosphorylation is not in treated with activity and PKCδ novel that PKCδ and Thr505 phosphorylation that PKCɛ PKCδ phosphorylation and that PKCδ phosphorylation PKCδ phosphorylation Thr505 not a PKCδ autophosphorylation PKCδ phosphorylation in in that PKCɛ PKCδ is in the PKCδ phosphorylation is in that a in PKCδ-Thr505 and phosphorylation in and In PKCɛ phosphorylation increases in PKCδ PKCδ as PKCɛ not that PKCδ is not in and that PKCɛ a in PKCδ phosphorylation in not increases PKCδ-Thr505 and phosphorylation in and used in and with the that PKCδ PKCδ kinase with PKCδ 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for a of AGC kinases we implicated a novel PKC activity in the in PKCδ-Thr505 phosphorylation in cardiomyocytes. 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phosphorylation requires activity PKCδ PKCɛ does not PKCδ-Thr505 phosphorylation in cardiomyocytes treated with and the in PKCδ-Thr505 phosphorylation is not in and it is the In the that PKCδ a Thr505 autophosphorylation that is in the of a of PKCδ that PKCδ controls PKCδ-Thr505 autophosphorylation in that PKCδ is and PKCɛ in that phosphorylation a in the of PKCδ activity. the of PKCδ-Thr505 phosphorylation not that PKCδ-Thr505 phosphorylation the of PKCδ that activation loop phosphorylation a mechanism the catalytic of PKCδ in a of in the of and PKCδ PKCɛ and PKCδ in in as and that PKCɛ that PKCɛ does not in the of PKC that of isoform of PKCɛ increases in PKCδ phosphorylation and a with the of PKCɛ the of PKCɛ and PKCδ in of the in that used in that PKCδ a of that PKCδ and Thr505 phosphorylation in not not in PKCδ or phosphorylation in the of a PKCδ and PKCδ of PKCδ in cardiomyocytes in as that PKCɛ PKCδ that of PKCɛ is in the the of PKCɛ PKCδ phosphorylation that of we a of that 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phosphorylation in not in that and is and that and with or and treated with or for as PKCδ-Thr505 via a and used a the PKCδ-Thr505 phosphorylation mechanism in and cardiomyocytes. that PKCδ a of Thr505 phosphorylation in PKCδ-Thr505 phosphorylation increases dynamically in with or increases in PKCδ-Thr505 phosphorylation PKC isoform not PKC the PKC kinase and phosphorylation require the of that with the the of that does not PKCδ-Thr505 implicate a activity in PKCδ-Thr505 the that PKCδ-Thr505 phosphorylation is we a of the of and PKC as in PKCδ-Thr505 of the of and that as a PKC and as of and activation loop phosphorylation PKCδ and in activation loop phosphorylation as a for is a activation loop phosphorylation for PKC activation loop phosphorylation is a or the and phosphorylation via has not been that increases phosphorylation via a mechanism that is a of does not and phosphorylation is not for and and implicate PKC as the that and PKCδ-Thr505 and phosphorylation via a mechanism that 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used as as with and require the phosphorylation in We that increases PKCδ phosphorylation via mechanism in cardiomyocytes that the increases in and phosphorylation not a in or activity that activation loop a for the in PKCδ-Thr505 phosphorylation requires PKCδ-Thr505 phosphorylation is not in treated with activity and PKCδ novel that PKCδ and Thr505 phosphorylation that PKCɛ PKCδ phosphorylation and that PKCδ phosphorylation PKCδ phosphorylation Thr505 not a PKCδ autophosphorylation PKCδ phosphorylation in in that PKCɛ PKCδ is in the PKCδ phosphorylation is in that a in PKCδ-Thr505 and phosphorylation in and In PKCɛ phosphorylation increases in PKCδ PKCδ as PKCɛ not that PKCδ is not in and that PKCɛ a in PKCδ phosphorylation in not cardiomyocytes. 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PKCδ-Thr505 phosphorylation as mechanism that is PKCδ and that PKCδ is cardiomyocytes with activation loop In contrast, PKCδ of activation loop phosphorylation in We of the enzyme the that PKCδ-Thr505 phosphorylation in show that and with of activation loop that PKCδ activity is not for PKCδ-Thr505 a of Thr505 for the of This phosphorylation is a of that with PKCδ the of PKCδ de novo enzyme synthesis. PKCδ-Thr505 phosphorylation is a for PKCδ autophosphorylation is not it is that as a PKCδ-Thr505 kinase study that used a PKCδ that catalytic activity In is that AGC as via mechanism in in and that is not for activation loop phosphorylation activation loop phosphorylation and enzyme activity in and PKCδ is in PKCδ is as a of a activation loop phosphorylation and the autophosphorylation that the enzyme In contrast, PKCɛ is for activation loop PKCɛ is not in with PKCδ the of PKCδ de novo enzyme that does not in the or α1-adrenergic mechanism that dynamically increases PKCδ-Thr505 phosphorylation in PKCδ-Thr505 phosphorylation is autophosphorylation or a phosphorylation We used as PKCɛ as a PKCδ-Thr505 show that PKCɛ a in PKCδ-Thr505 we of we that PKCɛ as a in PKCδ-Thr505 kinase in we a for mechanism that PKCɛ increases PKCδ-Thr505 phosphorylation via a mechanism and PKCδ we that PKCɛ increases PKCδ-Thr505 phosphorylation in with in PKCδ phosphorylation and We that the in PKCδ-Thr505 phosphorylation requires activity PKCδ PKCɛ does not PKCδ-Thr505 phosphorylation in cardiomyocytes treated with and the in PKCδ-Thr505 phosphorylation is not in and it is the In the that PKCδ a Thr505 autophosphorylation that is in the of a of PKCδ that PKCδ controls PKCδ-Thr505 autophosphorylation in that PKCδ is and PKCɛ in that phosphorylation a in the of PKCδ activity. the of PKCδ-Thr505 phosphorylation not that PKCδ-Thr505 phosphorylation the of PKCδ that activation loop phosphorylation a mechanism the catalytic of PKCδ in a of in the of and PKCδ PKCɛ and PKCδ in in as and that PKCɛ that PKCɛ does not in the of PKC that of isoform of PKCɛ increases in PKCδ phosphorylation and a with the of PKCɛ the of PKCɛ and PKCδ in of the in that used in that PKCδ a of that PKCδ and Thr505 phosphorylation in not not in PKCδ or phosphorylation in the of a PKCδ and PKCδ of PKCδ in cardiomyocytes in as that PKCɛ PKCδ that of PKCɛ is in the the of PKCɛ PKCδ phosphorylation that of we a of that isoform in of PKCɛ a PKCδ phosphorylation in and that the of PKCδ phosphorylation in a PKCɛ and the of PKCδ in the in in in of the not that PKCδ is PKCɛ and that PKCɛ in and Thr505 phosphorylation is not with in kinase or activity and a the of the of the mechanism that controls activation loop phosphorylation in study is that activation loop phosphorylation not been for AGC as PKCδ-Thr505 phosphorylation has as of PKCδ that PKCδ phosphorylation a novel a of PKCδ in PKCδ as enzyme that that the of controls activation loop PKCδ-Thr505 phosphorylation study that with and PKCδ as the as a activation loop kinase for a of AGC kinases we implicated a novel PKC activity in the in PKCδ-Thr505 phosphorylation in cardiomyocytes. 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PKCδ-Thr505 phosphorylation is a for PKCδ autophosphorylation is not it is that as a PKCδ-Thr505 kinase study that used a PKCδ that catalytic activity In is that AGC as via mechanism in in and that is not for activation loop phosphorylation activation loop phosphorylation and enzyme activity in and PKCδ is in PKCδ is as a of a activation loop phosphorylation and the autophosphorylation that the enzyme In contrast, PKCɛ is for activation loop PKCɛ is not in with PKCδ the of PKCδ de novo enzyme that does not in the or α1-adrenergic mechanism that dynamically increases PKCδ-Thr505 phosphorylation in PKCδ-Thr505 phosphorylation is autophosphorylation or a phosphorylation We used as PKCɛ as a PKCδ-Thr505 show that PKCɛ a in PKCδ-Thr505 we of we that PKCɛ as a in PKCδ-Thr505 kinase in we a for mechanism that PKCɛ increases PKCδ-Thr505 phosphorylation via a mechanism and PKCδ we that PKCɛ increases PKCδ-Thr505 phosphorylation in with in PKCδ phosphorylation and We that the in PKCδ-Thr505 phosphorylation requires activity PKCδ PKCɛ does not PKCδ-Thr505 phosphorylation in cardiomyocytes treated with and the in PKCδ-Thr505 phosphorylation is not in and it is the In the that PKCδ a Thr505 autophosphorylation that is in the of a of PKCδ that PKCδ controls PKCδ-Thr505 autophosphorylation in that PKCδ is and PKCɛ in that phosphorylation a in the of PKCδ activity. the of PKCδ-Thr505 phosphorylation not that PKCδ-Thr505 phosphorylation the of PKCδ that activation loop phosphorylation a mechanism the catalytic of PKCδ in a of in the of and PKCδ PKCɛ and PKCδ in in as and that PKCɛ that PKCɛ does not in the of PKC that of isoform of PKCɛ increases in PKCδ phosphorylation and a with the of PKCɛ the of PKCɛ and PKCδ in of the in that used in that PKCδ a of that PKCδ and Thr505 phosphorylation in not not in PKCδ or phosphorylation in the of a PKCδ and PKCδ of PKCδ in cardiomyocytes in as that PKCɛ PKCδ that of PKCɛ is in the the of PKCɛ PKCδ phosphorylation that of we a of that isoform in of PKCɛ a PKCδ phosphorylation in and that the of PKCδ phosphorylation in a PKCɛ and the of PKCδ in the in in in of the not that PKCδ is PKCɛ and that PKCɛ in and Thr505 phosphorylation is not with in kinase or activity and a the of the of the mechanism that controls activation loop phosphorylation in study is that activation loop phosphorylation not been for AGC as PKCδ-Thr505 phosphorylation has as of PKCδ that PKCδ phosphorylation a novel a of PKCδ in