PKCα and PKCδ: Friends and Rivals
2022; Elsevier BV; Volume: 298; Issue: 8 Linguagem: Inglês
10.1016/j.jbc.2022.102194
ISSN1083-351X
AutoresJennifer D. Black, Trisiani Affandi, Adrian R. Black, Mary E. Reyland,
Tópico(s)Diabetes Treatment and Management
ResumoPKC comprises a large family of serine/threonine kinases that share a requirement for allosteric activation by lipids. While PKC isoforms have significant homology, functional divergence is evident among subfamilies and between individual PKC isoforms within a subfamily. Here, we highlight these differences by comparing the regulation and function of representative PKC isoforms from the conventional (PKCα) and novel (PKCδ) subfamilies. We discuss how unique structural features of PKCα and PKCδ underlie differences in activation and highlight the similar, divergent, and even opposing biological functions of these kinases. We also consider how PKCα and PKCδ can contribute to pathophysiological conditions and discuss challenges to targeting these kinases therapeutically. PKC comprises a large family of serine/threonine kinases that share a requirement for allosteric activation by lipids. While PKC isoforms have significant homology, functional divergence is evident among subfamilies and between individual PKC isoforms within a subfamily. Here, we highlight these differences by comparing the regulation and function of representative PKC isoforms from the conventional (PKCα) and novel (PKCδ) subfamilies. We discuss how unique structural features of PKCα and PKCδ underlie differences in activation and highlight the similar, divergent, and even opposing biological functions of these kinases. We also consider how PKCα and PKCδ can contribute to pathophysiological conditions and discuss challenges to targeting these kinases therapeutically. PKC was discovered nearly 45 years ago based on its unique dependence on lipids and Ca2+ for activation (1Takai Y. Kishimoto A. Inoue M. Nishizuka Y. Studies on a cyclic nucleotide-independent protein kinase and its proenzyme in mammalian tissues. I. Purification and characterization of an active enzyme from bovine cerebellum.J. Biol. 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Kikkawa U. Igarashi K. Nishizuka Y. The structure, expression, and properties of additional members of the protein kinase C family.J. Biol. Chem. 1988; 263: 6927-6932Abstract Full Text PDF PubMed Google Scholar). PKC subfamilies have been defined based on specific requirements for activation by lipids and Ca2+. These subfamilies include conventional PKCs (cPKCs; PKCα, PKCβ, and PKCγ), which require diacylglycerol (DAG) and Ca2+ for activation, novel PKCs (nPKCs; PKCδ, PKCε, PKCη, and PKCθ), which are Ca2+ independent, and atypical PKCs (PKCζ and PKCι), which do not require DAG or Ca2+ and are activated by protein–protein interactions (6Mellor H. Parker P.J. The extended protein kinase C superfamily.Biochem. J. 1998; 332: 281-292Crossref PubMed Scopus (1354) Google Scholar). As many isoforms are ubiquitously expressed, targeting these kinases in disease has been daunting due in part to concerns about specificity and redundancy. This is the first review we are aware of that compares activation and function of representative isoforms of the cPKC (PKCα) and nPKC (PKCδ) subfamilies. Our goal is to highlight novel and unique aspects of the regulation and signaling functions of these isoforms to encourage their exploration as drug targets in cancer and other diseases. PKC isoforms participate in "outside–in" signaling by transducing signals from a variety of cell surface receptors including receptor tyrosine kinases (RTKs) and G protein–coupled receptors. Indeed, the identification of lipid-regulated kinases such as PKC was a turning point that linked hydrolysis of membrane inositol lipids, described decades earlier, to regulation of intracellular functions (7Hokin L.E. Hokin M.R. The incorporation of 32P into the nucleotides of ribonucleic acid in pigeon pancreas slices.Biochim. Biophys. Acta. 1953; 11: 591-592Crossref PubMed Scopus (7) Google Scholar, 8Meldrum E. Parker P.J. Carozzi A. The PtdIns-PLC superfamily and signal transduction.Biochim. Biophys. Acta. 1991; 1092: 49-71Crossref PubMed Scopus (157) Google Scholar). These receptors, as well as other physiologic activators of PKC, were shown to stimulate breakdown of membrane phosphatidylinositol 4,5-bisphosphate (PIP2) to generate the signaling lipids DAG and inositol 3-phosphate (IP3) (9Ganong B.R. Loomis C.R. Hannun Y.A. Bell R.M. Specificity and mechanism of protein kinase C activation by sn-1,2-diacylglycerols.Proc. Natl. Acad. Sci. U. S. A. 1986; 83: 1184-1188Crossref PubMed Google Scholar) (Fig. 1). DAG tethers PKC to the membrane, whereas IP3 induces release of Ca2+ from the endoplasmic reticulum (ER). Interaction of PKCs with the membrane induces conformational changes that lead to release of autoinhibition and activation. Thus, membrane localization is considered the hallmark of PKC activation (10Kraft A.S. Anderson W.B. Phorbol esters increase the amount of Ca2+, phospholipid-dependent protein kinase associated with plasma membrane.Nature. 1983; 301: 621-623Crossref PubMed Scopus (1000) Google Scholar) (see later and Refs. (4Newton A.C. Protein kinase C: structural and spatial regulation by phosphorylation, cofactors, and macromolecular interactions.Chem. Rev. 2001; 101: 2353-2364Crossref PubMed Scopus (832) Google Scholar, 11Rosse C. Linch M. Kermorgant S. Cameron A.J. Boeckeler K. Parker P.J. PKC and the control of localized signal dynamics.Nat. Rev. Mol. Cell Biol. 2010; 11: 103-112Crossref PubMed Scopus (341) Google Scholar) for a detailed description of PKC activation events). All PKC isoforms have highly conserved C-terminal catalytic domains and similar N-terminal regulatory domains (4Newton A.C. Protein kinase C: structural and spatial regulation by phosphorylation, cofactors, and macromolecular interactions.Chem. Rev. 2001; 101: 2353-2364Crossref PubMed Scopus (832) Google Scholar). However, divergence in critical motifs results in differences in cofactor requirements, mode of membrane recruitment, mechanisms of noncanonical activation, spatial distribution, desensitization, and protein–protein interactions. These differences underly the divergent functions that have been ascribed to PKC subfamilies and to isozymes within subfamilies (Fig. 2A). Later, we will discuss the unique structural features and known functions of PKCα (conventional subfamily) and PKCδ (novel subfamily) in diverse biological processes, highlighting contexts in which these kinases have contrasting and similar roles. The N-terminal domain of cPKC and nPKC isoforms includes a tandem repeat C1 domain comprising C1a and C1b subdomains that bind DAG, albeit with varying affinity, a membrane lipid–binding C2 domain, and a pseudosubstrate motif that blocks access to the substrate-binding pocket (12House C. Kemp B.E. Protein kinase C contains a pseudosubstrate prototope in its regulatory domain.Science. 1987; 238: 1726-1728Crossref PubMed Google Scholar). However, PKCs differ in the nature and arrangement of these domains. For example, in PKCα, the C2 domain lies between the C1 and catalytic domains, whereas in PKCδ, the C2 domain lies between the N terminus and the C1 domain (Fig. 2A). Elegant studies by several groups have revealed differences in the maturation, activation, and downregulation (inactivation) of PKCα and PKCδ that are thought to contribute to specification of function. Many AGC kinases share a requirement for serine/threonine phosphorylation at three conserved sites in the C-terminal domain for activity (3Leroux A.E. Schulze J.O. Biondi R.M. AGC kinases, mechanisms of regulation and innovative drug development.Semin. Cancer Biol. 2018; 48: 1-17Crossref PubMed Scopus (68) Google Scholar, 13Newton A.C. Regulation of the ABC kinases by phosphorylation: protein kinase C as a paradigm.Biochem. J. 2003; 370: 361-371Crossref PubMed Scopus (658) Google Scholar). In PKCs, constitutive phosphorylation in the activation loop by the PIP3-regulated kinase, 3-phosphoinositide-dependent protein kinase 1, transphosphorylation at the "turn" motif, typically by mammalian target of rapamycin complex 2 (mTORC2), and autophosphorylation at the hydrophobic motif (13Newton A.C. Regulation of the ABC kinases by phosphorylation: protein kinase C as a paradigm.Biochem. J. 2003; 370: 361-371Crossref PubMed Scopus (658) Google Scholar, 14Parekh D.B. Ziegler W. Parker P.J. Multiple pathways control protein kinase C phosphorylation.EMBO J. 2000; 19: 496-503Crossref PubMed Google Scholar, 15Le Good J.A. Ziegler W.H. Parekh D.B. Alessi D.R. Cohen P. Parker P.J. Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1.Science. 1998; 281: 2042-2045Crossref PubMed Scopus (971) Google Scholar) is required for catalytic competence and protection from degradation. It is important to emphasize that, in contrast to other AGC kinases that are acutely activated by phosphorylation (e.g., Akt (13Newton A.C. Regulation of the ABC kinases by phosphorylation: protein kinase C as a paradigm.Biochem. J. 2003; 370: 361-371Crossref PubMed Scopus (658) Google Scholar)), phosphorylation of the three "priming" sites is seen in inactive PKC (Fig. 2, B and C, step 2) and is, therefore, not indicative of PKC activation per se. Instead, membrane localization and substrate phosphorylation are the only reliable indicators of kinase activation. Comparison of the regulation and function of PKCα and PKCδ priming phosphorylation has revealed two important differences. First, unlike PKCα, which is dependent on activation loop phosphorylation for activity (14Parekh D.B. Ziegler W. Parker P.J. Multiple pathways control protein kinase C phosphorylation.EMBO J. 2000; 19: 496-503Crossref PubMed Google Scholar), the T505A activation loop mutant of PKCδ is still partially active (16Stempka L. Girod A. Muller H.J. Rincke G. Marks F. Gschwendt M. et al.Phosphorylation of protein kinase Cdelta (PKCdelta) at threonine 505 is not a prerequisite for enzymatic activity. Expression of rat PKCdelta and an alanine 505 mutant in bacteria in a functional form.J. Biol. Chem. 1997; 272: 6805-6811Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar). This difference may have consequences for modulation of kinase activity as well as kinase degradation. Second, a recent study from the Newton laboratory has identified a fourth priming phosphorylation motif, the mTOR interaction motif, in some mTORC2–regulated AGC kinases, including PKCα (17Baffi T.R. Lorden G. Wozniak J.M. Feichtner A. Yeung W. Kornev A.P. et al.mTORC2 controls the activity of PKC and Akt by phosphorylating a conserved TOR interaction motif.Sci. Signal. 2021; 14eabe4509Crossref PubMed Scopus (26) Google Scholar, 18Baffi T.R. Newton A.C. mTOR regulation of AGC kinases: new twist to an old tail.Mol. Pharmacol. 2021; 101: 213-218Crossref PubMed Scopus (0) Google Scholar). Phosphorylation of this motif (S631 in PKCα) by the mTORC2 complex allosterically regulates PIP3-regulated kinase, 3-phosphoinositide-dependent protein kinase 1 binding, activation loop phosphorylation, and autophosphorylation of the hydrophobic motif. Curiously, select nPKC isoforms, including PKCδ, are mTORC2 independent for priming and lack this conserved threonine (19Ikenoue T. Inoki K. Yang Q. Zhou X. Guan K.L. Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling.EMBO J. 2008; 27: 1919-1931Crossref PubMed Scopus (498) Google Scholar). Additional serine and threonine phosphorylation events may fine-tune activation of PKCδ in response to specific signals (20Gong J. Holewinski R.J. Van Eyk J.E. Steinberg S.F. A novel phosphorylation site at Ser130 adjacent to the pseudosubstrate domain contributes to the activation of protein kinase C-delta.Biochem. J. 2015; 473: 311-320Crossref PubMed Scopus (5) Google Scholar). As discussed later, tyrosine phosphorylation may in addition play a role in modulating the activity of PKCα and PKCδ. Divergence in the C2 and C1 domains of PKCα and PKCδ accounts for important differences in Ca2+ dependence and mechanism of activation (Fig. 2). C2 domains are evolutionary conserved lipid-and protein-binding motifs (21Corbalan-Garcia S. Gomez-Fernandez J.C. Signaling through C2 domains: more than one lipid target.Biochim. Biophys. Acta. 2014; 1838: 1536-1547Crossref PubMed Scopus (141) Google Scholar). 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The C2 domain of PKCdelta is a phosphotyrosine binding domain.Cell. 2005; 121: 271-280Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar) have identified a novel high-affinity phosphotyrosine-binding (PTB) motif in the PKCδ C2 domain, which is not found in PKCα or other PKC isozymes. This PTB domain is distinct from both Src-homology 2 and previously described PTB domains in that it interacts with residues in the phosphorylated peptide both C-terminal and N-terminal to pTyr (22Benes C.H. Wu N. Elia A.E. Dharia T. Cantley L.C. Soltoff S.P. The C2 domain of PKCdelta is a phosphotyrosine binding domain.Cell. 2005; 121: 271-280Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar). Binding of the C2 PTB domain to phosphotyrosine-containing proteins in trans could drive the formation of PKCδ-specific signaling modules, whereas cis interactions could contribute to regulation of PKCδ by binding to tyrosine-phosphorylated residues within the kinase domain, for example, as induced by hydrogen peroxide (25Konishi H. Tanaka M. Takemura Y. Matsuzaki H. Ono Y. Kikkawa U. et al.Activation of protein kinase C by tyrosine phosphorylation in response to H2O2.Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 11233-11237Crossref PubMed Scopus (535) Google Scholar). cPKC and nPKC C1a and C1b domains differ in their affinity for DAG and play unique roles in isoform activation (26Li J. Ziemba B.P. Falke J.J. Voth G.A. Interactions of protein kinase C-alpha C1A and C1B domains with membranes: a combined computational and experimental study.J. Am. Chem. Soc. 2014; 136: 11757-11766Crossref PubMed Scopus (0) Google Scholar). 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Interplay of C1 and C2 domains of protein kinase C-α; in its membrane binding and activation ∗.J. Biol. Chem. 1999; 274: 19852-19861Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 31Ziemba B.P. Li J. Landgraf K.E. Knight J.D. Voth G.A. Falke J.J. Single-molecule studies reveal a hidden key step in the activation mechanism of membrane-bound protein kinase C-alpha.Biochemistry. 2014; 53: 1697-1713Crossref PubMed Scopus (35) Google Scholar, 32Lipp P. Reither G. Protein kinase C: the "masters" of calcium and lipid.Cold Spring Harb. Perspect. Biol. 2011; 3a004556Crossref PubMed Scopus (56) Google Scholar). Notably, although the C2 domain of PKCα has low intrinsic affinity for Ca2+, its Ca2+ binding is enhanced by PIP2, phosphatidylserine, and DAG in the plasma membrane, allowing for enzyme activation by DAG even at subphysiological intracellular Ca2+ levels (21Corbalan-Garcia S. Gomez-Fernandez J.C. Signaling through C2 domains: more than one lipid target.Biochim. 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The mechanism of PKCδ activation is similar to that of PKCα, except that PKCδ does not bind calcium and is targeted to the membrane primarily through high-affinity binding of the C1 domains to membrane DAG (37Giorgione J.R. Lin J.H. McCammon J.A. Newton A.C. Increased membrane affinity of the C1 domain of protein kinase Cdelta compensates for the lack of involvement of its C2 domain in membrane recruitment.J. Biol. Chem. 2006; 281: 1660-1669Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar) (Fig. 2C). However, the relative contribution of the C1a and C1b domains to membrane DAG binding remains to be resolved. It has been reported that, as in PKCα, the C1a domain of PKCδ has high affinity for DAG, whereas the C1b domain fails to bind DAG but has high affinity for phorbol esters (38Stahelin R.V. Digman M.A. Medkova M. Ananthanarayanan B. Rafter J.D. Melowic H.R. et al.Mechanism of diacylglycerol-induced membrane targeting and activation of protein kinase Cdelta.J. Biol. 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Nonetheless, the high affinity of the C1 domain of PKCδ for DAG compensates for the lack of membrane binding of its C2 domain, allowing for direct C2 domain–independent membrane recruitment and activation of the kinase by signal-generated DAG (37Giorgione J.R. Lin J.H. McCammon J.A. Newton A.C. Increased membrane affinity of the C1 domain of protein kinase Cdelta compensates for the lack of involvement of its C2 domain in membrane recruitment.J. Biol. Chem. 2006; 281: 1660-1669Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar). DAG-independent functions of the C1b domain may also contribute to targeting and activation of PKCδ (37Giorgione J.R. Lin J.H. McCammon J.A. Newton A.C. Increased membrane affinity of the C1 domain of protein kinase Cdelta compensates for the lack of involvement of its C2 domain in membrane recruitment.J. Biol. Chem. 2006; 281: 1660-1669Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar). For instance, Wang et al. (40Wang H. Xiao L. Kazanietz M.G. p23/Tmp21 associates with protein kinase Cdelta (PKCdelta) and modulates its apoptotic function.J. Biol. Chem. 2011; 286: 15821-15831Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar) have shown that the C1b domain of PKCδ mediates its association with the Golgi/ER protein, p23/Tmp21, to regulate apoptosis. In addition to the plasma membrane, it is now clear that PKC isoforms can be activated in a variety of subcellular locations and can respond to stimuli that do not promote hydrolysis of membrane lipids (41Scott J.D. Newton A.C. Shedding light on local kinase activation.BMC Biol. 2012; 10: 61Crossref PubMed Scopus (0) Google Scholar). One well-documented mechanism of noncanonical activation of both cPKCs and nPKCs is through reactive oxygen species (ROS) (42Steinberg S.F. Mechanisms for redox-regulation of protein kinase C.Front. Pharmacol. 2015; 6: 128Crossref PubMed Scopus (66) Google Scholar). The cysteine-rich zinc-binding finger of C1 domains is highly sensitive to oxidation by ROS, which destroys the conformation of the DAG-binding site. For PKC, oxidation by ROS typically relieves autoinhibition and activates the kinase (43Cosentino-Gomes D. Rocco-Machado N. Meyer-Fernandes J.R. Cell signaling through protein kinase C oxidation and activation.Int. J. Mol. Sci. 2012; 13: 10697-10721Crossref PubMed Scopus (160) Google Scholar). While redox-dependent conformational changes can activate both cPKCs and nPKCs, PKCδ can also be regulated by oxidative stress through changes in phosphorylation of specific tyrosine residues unique to this isoform (25Konishi H. Tanaka M. Takemura Y. Matsuzaki H. Ono Y. Kikkawa U. et al.Activation of protein kinase C by tyrosine phosphorylation in response to H2O2.Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 11233-11237Crossref PubMed Scopus (535) Google Scholar, 44Konishi H. Yamauchi E. Taniguchi H. Yamamoto T. Matsuzaki H. Takemura Y. et al.Phosphorylation sites of protein kinase C delta in H2O2-treated cells and its activation by tyrosine kinase in vitro.Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 6587-6592Crossref PubMed Scopus (0) Google Scholar). There are at least two explanations for redox regulation via tyrosine phosphorylation (42Steinberg S.F. Mechanisms for redox-regulation of protein kinase C.Front. Pharmacol. 2015; 6: 128Crossref PubMed Scopus (66) Google Scholar). First, cysteine residues in the active site of protein tyrosine phosphatases are very sensitive to redox inactivation, and the inhibition of dephosphorylation manifests as an overall increase in tyrosine phosphorylation (45Chiarugi P. Taddei M.L. Ramponi G. Oxidation and tyrosine phosphorylation: synergistic or antagonistic cues in protein tyrosine phosphatase.Cell Mol. Life Sci. 2005; 62: 931-936Crossref PubMed Scopus (0) Google Scholar). Second, redox activation of RTKs (e.g., epidermal growth factor receptor [EGFR]) and non-RTKs (e.g., c-Abl, c-Src, and Src-family kinases) results in increased phosphorylation on tyrosine residues in PKCδ (42Steinberg S.F. Mechanisms for redox-regulation of protein kinase C.Front. Pharmacol. 2015; 6: 128Crossref PubMed Scopus (66) Google Scholar, 46Truong T.H. Carroll K.S. Redox regulation of epidermal growth factor receptor signaling through cysteine oxidation.Biochemistry. 2012; 51: 9954-9965Crossref PubMed Scopus (128) Google Scholar). The most extensively studied of these residues are Tyr311 (rodent; 313 human), Tyr155 (rodent and human), and Tyr64 (rodent and human), which can be phosphorylated by c-Lck, c-Abl, and c-Src (25Konishi H. Tanaka M. Takemura Y. Matsuzaki H. Ono Y. Kikkawa U. et al.Activation of protein kinase C by tyrosine phosphorylation in response to H2O2.Proc. Natl. Acad. Sci. U. S. 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