The 14-3-3 protein is a family of highly conserved acidic proteins found in a wide range of eukaryotes from yeast to mammals. 14-3-3 acts as an adapter protein and interacts with signaling molecules including protein kinase C (PKC). Although 14-3-3 ζ was originally characterized as an endogenous PKC inhibitor, it was reported to activate PKC in vitro, but the in vivo regulation of PKC by 14-3-3 is still not well understood. To examine the regulation of PKC by 14-3-3 in the cell, we have generated a sub-cell line, PC12-B3, that stably expresses FLAG epitope-tagged 14-3-3 ζ isoform in PC12 cells. Here we show that PKC-α and PKC-ε become associated with 14-3-3 ζ when the cells are neuronally differentiated by nerve growth factor. We found that the immunoprecipitate by anti-FLAG antibody contains constitutive and autonomous Ca2+-independent non-classical PKC activity. In contrast, the FLAG immunoprecipitate has no Ca2+-dependent classical PKC activity despite the fact that PKC-α is present in the FLAG immunoprecipitate from differentiated PC12-B3 cells. Our results show that the association with 14-3-3 ζ has distinct effects on classical PKC and non-classical PKC activity. The 14-3-3 protein is a family of highly conserved acidic proteins found in a wide range of eukaryotes from yeast to mammals. 14-3-3 acts as an adapter protein and interacts with signaling molecules including protein kinase C (PKC). Although 14-3-3 ζ was originally characterized as an endogenous PKC inhibitor, it was reported to activate PKC in vitro, but the in vivo regulation of PKC by 14-3-3 is still not well understood. To examine the regulation of PKC by 14-3-3 in the cell, we have generated a sub-cell line, PC12-B3, that stably expresses FLAG epitope-tagged 14-3-3 ζ isoform in PC12 cells. Here we show that PKC-α and PKC-ε become associated with 14-3-3 ζ when the cells are neuronally differentiated by nerve growth factor. We found that the immunoprecipitate by anti-FLAG antibody contains constitutive and autonomous Ca2+-independent non-classical PKC activity. In contrast, the FLAG immunoprecipitate has no Ca2+-dependent classical PKC activity despite the fact that PKC-α is present in the FLAG immunoprecipitate from differentiated PC12-B3 cells. Our results show that the association with 14-3-3 ζ has distinct effects on classical PKC and non-classical PKC activity. protein kinase C non-classical PKC classical PKC nerve growth factor 12-O-tetradecanoylphorbol-13-acetate The 14-3-3 protein, a family of acidic 30-kDa proteins, is ubiquitous and highly enriched in the central nervous system (1Aitken A. Collinge D.B. van Heusden B.P. Isobe T. Roseboom P.H. Rosenfeld G. Soll J. Trends Biochem. Sci. 1992; 17: 498-501Abstract Full Text PDF PubMed Scopus (434) Google Scholar). It is estimated that ∼1% of the total cytosolic proteins expressed in the mammalian brain is 14-3-3 (2Aitken A. Amess B. Howell S. Jones D. Martin H. Patel Y. Robinson K. Toker A. Biochem. Soc. Trans. 1992; 20: 607-611Crossref PubMed Scopus (15) Google Scholar). 14-3-3 acts as an adapter protein and interacts with signaling molecules to mediate a wide variety of cellular events such as cell cycle regulation, cell growth and differentiation, anti-apoptosis, and synaptic transmission (For review, see Refs. 3Russell P. Trends Biochem. Sci. 1998; 23: 399-402Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 4Skoulakis E.M. Davis R.L. Mol. Neurobiol. 1998; 16: 269-284Crossref PubMed Scopus (134) Google Scholar, 5Fu H. Subramanian R.R. Masters S.C. Annu. Rev. Pharmacol. Toxicol. 2000; 40: 617-647Crossref PubMed Scopus (1328) Google Scholar). The 14-3-3 protein is conserved among species ranging from yeast to human and normally exists as a dimer. In the brain cytosol, seven 14-3-3 subspecies (α, β, γ, δ, ε, η, and ζ) were chromatographically separated, and of these, α and δ were found to be phosphorylated forms of β and ζ, respectively (6Aitken A. Howell S. Jones D. Madrazo J. Patel Y. J. Biol. Chem. 1995; 270: 5706-5709Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar). In addition, the θ isoform was also found in the rat brain (7Watanabe M. Isobe T. Ichimura T. Kuwano R. Takahashi Y. Kondo H. Inoue Y. Brain Res. Mol. Brain Res. 1994; 25: 113-121Crossref PubMed Scopus (69) Google Scholar) and was originally discovered in the T cell line as 14-3-3 τ (8Nielsen P.J. Biochim. Biophys. Acta. 1991; 1088: 425-428Crossref PubMed Scopus (51) Google Scholar). Thus, at least six 14-3-3 isoforms are present in the mammalian brain. leonardo, a Drosophila gene homologue of the vertebrate 14-3-3 ζ, is expressed in abundance in mushroom bodies, and mutants with low levels of expression of leonardo show deficiency in olfactory learning (9Skoulakis E.M. Davis R.L. Neuron. 1996; 17: 931-944Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar). The Leonardo protein is also highly enriched in the presynaptic boutons in the fly neuromuscular junction (10Broadie K. Rushton E. Skoulakis E.M. Davis R.L. Neuron. 1997; 19: 391-402Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar). Significant reduction of glutamate synaptic transmission has been observed at the neuromuscular junctions ofleonardo (−/−) null mutant larvae, and this effect is attributed to a presynaptic mechanism (10Broadie K. Rushton E. Skoulakis E.M. Davis R.L. Neuron. 1997; 19: 391-402Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar). Consistent with this notion, the Leonardo protein was recently shown inDrosophila neuromuscular junction to form a complex with the Ca 2+ -dependent K+channel, Slowpoke, at the presynaptic nerve terminals (11Zhou Y. Schopperle W.M. Murrey H. Jaramillo A. Dagan D. Griffith L.C. Levitan I.B. Neuron. 1999; 22: 809-818Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar). Although very little is known regarding the function of vertebrate 14-3-3 ζ in neuronal cells, several lines of evidence indicate that it plays a role in synaptic function in vertebrates as well. Immunological and biochemical studies show that mammalian 14-3-3 ζ localizes in synapses in the rat brain (12Martin H. Rostas J. Patel Y. Aitken A. J. Neurochem. 1994; 63: 2259-2265Crossref PubMed Scopus (147) Google Scholar). The 14-3-3 protein was involved in exocytosis; it stimulates Ca 2+ -dependent catecholamine release from digitonin-permeabilized adrenal chromaffin cells (13Morgan A. Burgoyne R.D. Nature. 1992; 355: 833-836Crossref PubMed Scopus (159) Google Scholar, 14Morgan A. Burgoyne R.D. Biochem. J. 1992; 286: 807-811Crossref PubMed Scopus (64) Google Scholar, 15Burgoyne R.D. Morgan A. Robinson I. Pender N. Cheek T.R. J. Anat. 1993; 183: 309-314PubMed Google Scholar), in which 14-3-3 ζ is one of the major isoforms (16Roth D. Morgan A. Martin H. Jones D. Martens G.J. Aitken A. Burgoyne R.D. Biochem. J. 1994; 301: 305-310Crossref PubMed Scopus (59) Google Scholar). One of the target molecules of 14-3-3 is protein kinase C (PKC).1 14-3-3, originally discovered as an activator protein for tyrosine hydroxylase and tryptophan hydroxylase (17Yamauchi T. Nakata H. Fujisawa H. J. Biol. Chem. 1981; 256: 5404-5409Abstract Full Text PDF PubMed Google Scholar), was isolated as an endogenouskinase Cinhibitoryprotein (KCIP) (18Toker A. Ellis C.A. Sellers L.A. Aitken A. Eur. J. Biochem. 1990; 191: 421-429Crossref PubMed Scopus (186) Google Scholar). It was later found that KCIP was identical to the 14-3-3 protein (19Toker A. Sellers L.A. Amess B. Patel Y. Harris A. Aitken A. Eur. J. Biochem. 1992; 206: 453-461Crossref PubMed Scopus (123) Google Scholar). However, it has been reported that 14-3-3 ζ activates rather than inhibits PKC in vitro(20Isobe T. Hiyane Y. Ichimura T. Okuyama T. Takahashi N. Nakajo S. Nakaya K. FEBS Lett. 1992; 308: 121-124Crossref PubMed Scopus (79) Google Scholar, 21Tanji M. Horwitz R. Rosenfeld G. Waymire J.C. J. Neurochem. 1994; 63: 1908-1916Crossref PubMed Scopus (52) Google Scholar). Thus, although 14-3-3 was initially characterized as a PKC inhibitor, its effect on PKC is still not clear. Because PKC is critical for neuronal differentiation in PC12 cells (22Hundle B. McMahon T. Dadgar J. Messing R.O. J. Biol. Chem. 1995; 270: 30134-30140Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, B. McMahon T. Dadgar J. D. Messing R.O. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, D. L.A. I.B. Mol. Biol. 1995; PubMed Scopus Google Scholar, J. Mol. 1994; PubMed Scopus Google Scholar, K. P. P. G. 1999; Google Scholar), we have the PKC and 14-3-3 ζ and it the PKC activity in neuronal cells. this we have a sub-cell line of PC12 cells that stably FLAG epitope-tagged 14-3-3 Here we show the association of 14-3-3 ζ with PKC-α and PKC-ε in differentiated PC12-B3 cells. we found that the 14-3-3 ζ immunoprecipitate by anti-FLAG antibody from the cells contains Ca2+-independent non-classical PKC activity. is and not of PKC constitutive of in the 14-3-3 ζ complex an role in neuronal differentiation of PC12 cells by 14-3-3 ζ isolated from rat K. 1996; PubMed Scopus Google Scholar) and in mammalian expression was for the FLAG was at the C of 14-3-3 ζ and at of as 14-3-3 ζ was by as a with a and with The was and and in at of the was by 14-3-3 ζ has protein forms and K. 1996; PubMed Scopus Google Scholar). To which 14-3-3 ζ is expressed in PC12 cells, we from PC12 cells was isolated and for by 14-3-3 ζ was by and PC12 cells were in of with and in a at L.A. G. K. Scholar). The was and a PC12 cells and its sub-cell line PC12-B3, which expresses FLAG epitope-tagged 14-3-3 ζ, were differentiated by cells were in a and in the cells were with of and in of for the of the was and with the of of and of and at for was for a of and for this the was with with and and the cells were for PC12 sub-cell lines that stably FLAG epitope-tagged 14-3-3 ζ were on the The cells were in the of for and the cells were and in a in was by a E. D. Scholar). ζ and PKC were for the were as the and the was the In that we and by The were at on were with were for cell and for The cell was and at for To the cell the was with of protein for and for at were with a antibody for with and protein were for and at The were and with The activity of PKC of the with FLAG antibody from differentiated cells was PKC that were for Ca2+-dependent activity and for Ca2+-independent non-classical and PKC and The FLAG for PKC were from cell in The were with at and to with of the was to PKC activity in the of with the of Ca 2+ PKC and PKC as in the Ca2+-dependent was for the at Ca 2+ was in the of Ca 2+ as a PKC in the of The of PKC was on the in and is a of and and be phosphorylated by but it is a for Ca 2+ S.C. D. S. P.J. Biochem. Soc. Trans. 1992; 20: PubMed Scopus Google Scholar). In contrast, activity is but it S.C. D. S. P.J. Biochem. Soc. Trans. 1992; 20: PubMed Scopus Google Scholar). total Ca 2+ to Ca 2+ were by of with and Biochem. 1992; PubMed Scopus Google Scholar). was by to a in a total of a at protein in the was by of the was and the was the Our that are several of 14-3-3 ζ from mammalian brain. are of the at at and at In the rat and 14-3-3 ζ are present K. 1996; PubMed Scopus Google Scholar). Because the 14-3-3 protein to a variety of signaling molecules and acts as an protein, have effects on proteins for the To the to the 14-3-3 ζ protein we have the endogenous 14-3-3 ζ in PC12 cells by that endogenous 14-3-3 ζ contains and at the We have a FLAG to this 14-3-3 ζ and expressed the in PC12 cells. To PC12 sub-cell lines that stably the ζ, cells were initially with and the cells were and To the epitope-tagged 14-3-3 ζ, were by FLAG and 14-3-3 14-3-3 ζ antibody and the anti-FLAG antibody the in that FLAG epitope-tagged 14-3-3 ζ not that the 30-kDa protein is the endogenous 14-3-3 ζ, protein is the 14-3-3 ζ with the to the of a FLAG was no in one of the sub-cell line, in and the to from the PC12 cells. We PC12-B3 as a PC12 that stably expresses epitope-tagged 14-3-3 To the 14-3-3 ζ and we the PKC isoforms that are expressed in PC12-B3 cells and its PC12 cell Significant and were but we not and in PC12-B3 in the PC12 cell line Because PKC has been shown to a role in neuronal as well as PC12 cell differentiation, we have to the 14-3-3 ζ association with PKC is in differentiated cells when with cells. We PKC-ε it is among the PKC isoforms critical for PC12 cell differentiation (22Hundle B. McMahon T. Dadgar J. Messing R.O. J. Biol. Chem. 1995; 270: 30134-30140Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, B. McMahon T. Dadgar J. D. Messing R.O. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google K. P. P. G. 1999; Google Scholar, M. G. Biochem. J. 1993; PubMed Scopus Google Scholar). shown in PKC-ε with ζ in differentiated PC12-B3 cells but not in cells. The antibody contains ζ the anti-FLAG antibody immunoprecipitate contains PKC-ε in the differentiated cells. In contrast, of PKC-ε and ζ be from cells, are present in cells, and the levels of expression of 14-3-3 ζ and PKC-ε of PKC in PC12-B3 cells and association with 14-3-3 ζ in and differentiated in PC12-B3 with 14-3-3 in a To examine PKC-ε not with the 14-3-3 ζ but also with the endogenous 14-3-3 ζ in a on neuronal differentiation, we ζ antibody from and PC12 cells. shown in endogenous 14-3-3 ζ with PKC-ε from cells, but the is not from PC12 cells. Thus, PKC-ε interacts with the ζ as well as with the endogenous 14-3-3 ζ in neuronally differentiated PC12 cells but not in cells. One of the regarding the association of PKC-ε with 14-3-3 ζ is this complex is by the by it is a of the differentiated of PC12 cells. To we the of the complex of PKC-ε and 14-3-3 ζ by FLAG from PC12 cells with with a of to of PKC-ε and FLAG 14-3-3 ζ be of as shown in of the association that the complex is not to the effect of of but it is associated at the differentiation of PC12 cells. We have the ζ is to this PKC the found in this sub-cell line, we have found that δ, and isoforms also with as shown in However, the of PKC isoforms with 14-3-3 ζ is with to and isoforms were with FLAG antibody of differentiation, that with 14-3-3 ζ is also present in the FLAG from and differentiated cells. However, the association of with ζ a differentiation that the of this PKC isoform with 14-3-3 ζ also be to neuronal to the and of PKC-α with 14-3-3 ζ be when the cells were neuronally We not PKC-α in the FLAG immunoprecipitate from cells, that this isoform is not present in the immunoprecipitate the is low for Thus, the PKC-α and 14-3-3 ζ in PC12-B3 cells on the of show that PKC isoforms to 14-3-3 ζ in a as well as The results are in I. The FLAG immunoprecipitate contains several PKC Ca 2+ -dependent PKC-α and Ca 2+ and in PC12-B3 cells. To Ca 2+ -dependent and Ca 2+ PKC we that PKC in the FLAG as we the PKC activity in the FLAG from differentiated and PC12 cells. PC12 cells that not FLAG epitope-tagged 14-3-3 ζ was as a shown in Ca 2+ PKC activity was in the immunoprecipitate from cells, in the of PKC activity be by but to the by a kinase by a In contrast, the immunoprecipitate from cells has no Ca 2+ PKC activity. results show that 14-3-3 complex in differentiated cells has constitutive and autonomous Ca 2+ the complex in cells not have activity of to and of the activity in FLAG immunoprecipitate from PC12-B3 cells. to and of the constitutive and autonomous activity found in the FLAG immunoprecipitate from differentiated cells. The activity was by and by of activity and of are a Ca 2+ -dependent associated with 14-3-3 ζ neuronal differentiation by However, was no Ca2+-dependent PKC activity in the immunoprecipitate of differentiation as shown in has no effect on the PKC activity. The of activity in the is not to a of the of PKC-α be in this system as shown in Because isoforms are not present in the FLAG results that PKC-α associated with 14-3-3 ζ in differentiated cells is and to PKC However, it is that the of activity be to an of PKC-α present in the immunoprecipitate that was for To examine we have in which we the of PKC-α in the immunoprecipitate by with known of PKC-α to the of the and kinase activity in the shown in the immunoprecipitate for and shown in of was no observed for PKC-α to The of PKC-α at least of the on the of PKC-α in the for was estimated to be The activity of PKC-α be as low as in the activity for the not the the 14-3-3 ζ immunoprecipitate in is at the on we that the PKC-α is in the immunoprecipitate from differentiated PC12 of PKC in the 14-3-3 ζ immunoprecipitate by to the of PKC-α in the immunoprecipitate from differentiated PC12 cells, immunoprecipitate and of PKC-α for were by by and for shown in and immunoprecipitate from differentiated PC12 cells in of for a at of PKC-α the as in A. activity of immunoprecipitate from differentiated PC12 in a In to PKC be by such as L.C. R. PubMed Scopus Google Scholar, K. A. J. Biol. Chem. Full Text PDF PubMed Google Scholar, K. Biochem. J. 1992; PubMed Scopus Google Scholar). is a activator of PKC-ε in H. K. Y. Sci. S. A. 1992; PubMed Scopus Google Scholar) and stimulates the of PKC-ε in cells Y. J. Sci. 1997; Google Scholar, Y. K. K. N. N. J. Biol. 1998; PubMed Scopus (123) Google Scholar). In contrast, activates H. K. Y. Sci. S. A. 1992; PubMed Scopus Google Scholar) the isoform in cells Y. J. Sci. 1997; Google Scholar). Because and are the non-classical that become associated association with 14-3-3 ζ in differentiated PC12-B3 cells, we to activity found in the FLAG immunoprecipitate from differentiated cells is to shown in activity in the of Ca 2+ and this activity was by that PKC-ε is the for the constitutive activity. we found that the Ca 2+ PKC activity in the FLAG immunoprecipitate be by low of Ca 2+ but it is by Ca 2+ an that Ca 2+ not classical PKC but also non-classical PKC when it is associated with 14-3-3 PKC has been as one of the of 14-3-3, but the of the PKC association with 14-3-3 is still In this we have 14-3-3 ζ interacts with vivo in neuronal cells PC12 and its cell line that stably expresses epitope-tagged 14-3-3 We have shown that several PKC isoforms with 14-3-3 ζ in PC12-B3 cells. of PKC-α and is not with 14-3-3 ζ in cells but become associated with 14-3-3 ζ when the cells are neuronally differentiated by to this and isoforms were found to with 14-3-3 ζ of the of cell differentiation, although the association of with 14-3-3 ζ differentiation to Significant Ca 2+ PKC activity is present in FLAG immunoprecipitate from differentiated cells, but it is not in the immunoprecipitate from cells although and isoforms are results indicate that the effect of 14-3-3 ζ on PKC in cells is from observed in effect of 14-3-3 on PKC has been as to it activates inhibits the activity of PKC by 14-3-3 was shown to be to the acidic of 14-3-3, and it was that in activity not with in of PKC by 14-3-3 J.C. P. J. Biochem. J. 2000; PubMed Scopus Google Scholar). Although in of the association of 14-3-3 with PKC is rather several 14-3-3 isoforms were shown to with in cells and in in the of a complex with J.C. P. J. Biochem. J. 2000; PubMed Scopus Google Scholar). In T cells, 14-3-3 τ was shown to the activity of N. N. G. N. A. Mol. Biol. 1996; 16: PubMed Google Scholar) and A. P. G. H. A. K. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). Our neuronal cells that 14-3-3 form of PKC has on the However, it be that not indicate the regulation of is a of the 14-3-3 ζ and PKC The FLAG immunoprecipitate from differentiated PC12-B3 cells contains constitutive activity. that of the non-classical PKC is in cells when it is associated with and in to PKC-ε are the non-classical PKC isoforms found in the FLAG immunoprecipitate from differentiated PC12-B3 cells. PKC is for the constitutive activity in the FLAG and are also present in the FLAG immunoprecipitate from cells However, the PKC activity of the immunoprecipitate is not from the activity in the FLAG immunoprecipitate from PC12 cells, which not FLAG epitope-tagged 14-3-3 ζ that PKC isoforms to 14-3-3 ζ are that association with 14-3-3 ζ is to the activity. It is that the activity of PKC to 14-3-3 ζ become in differentiated cells by an However, it is that the activity found in the FLAG immunoprecipitate from differentiated cells is to PKC-ε for the PKC-ε and are the isoforms that association with 14-3-3 ζ activates and is to H. K. Y. Sci. S. A. 1992; PubMed Scopus Google Scholar, Y. J. Sci. 1997; Google Scholar). Our that the constitutive activity is to that PKC-ε is for the constitutive activity in differentiated PC12 cells. PKC-ε has been shown to be by 14-3-3 ζ the PKC isoforms in P. Biochem. Biophys. Res. 1995; PubMed Scopus Google Scholar), although it is not this in effect is to vivo of PKC-ε in the 14-3-3 ζ In to D. L.A. I.B. Mol. Biol. 1995; PubMed Scopus Google Scholar, Mol. Biol. 1999; 19: PubMed Google Scholar, H. 1998; PubMed Scopus Google Scholar) and G. 1994; Google Scholar), PKC-ε has been to a role in in PC12 cells (22Hundle B. McMahon T. Dadgar J. Messing R.O. J. Biol. Chem. 1995; 270: 30134-30140Abstract Full Text Full Text PDF PubMed Scopus (117) Google B. McMahon T. Dadgar J. D. Messing R.O. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, K. P. P. G. 1999; Google Scholar) as well as in cells S. S. E. 1996; Google Scholar, S. G. E. S. J. Res. 1995; PubMed Scopus Google Scholar). PKC by low of has been shown to neuronal differentiation of human cells S. S. E. 1996; Google Scholar). S. G. E. S. J. 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Biol. 1997; PubMed Scopus Google Scholar) show that the 14-3-3 to this PKC the of the PKC and that this inhibits PKC activity. 14-3-3 to the expressed in the in vivo the and this to the cells to the release of PKC that an mechanism to the 14-3-3 of PKC the is the of Because which not have the 14-3-3 associated with 14-3-3 ζ differentiation of PC12-B3 cells, such a mechanism the studies are to the mechanism of mammalian PKC and In we have shown that several PKC isoforms with 14-3-3 ζ in PC12-B3 cells. of PC12-B3 cells by association of PKC with 14-3-3 ζ to α and PKC and the association with 14-3-3 ζ has distinct effects on and activity. We and for in the of this We the for the of for the of
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