The maturing mutational landscape of cancer genomes, the development and application of clinical interventions and evolving insights into tumour-associated functions reveal unexpected features of the protein kinase C (PKC) family of serine/threonine protein kinases. These advances include recent work showing gain or loss-of-function mutations relating to driver or bystander roles, how conformational constraints and plasticity impact this class of proteins and how emergent cancer-associated properties may offer opportunities for intervention. The profound impact of the tumour microenvironment, reflected in the efficacy of immune checkpoint interventions, further prompts to incorporate PKC family actions and interventions in this ecosystem, informed by insights into the control of stromal and immune cell functions. Drugging PKC isoforms has offered much promise, but when and how is not obvious.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Manning, G., Whyte, D. B., Martinez, R., Hunter, T. & Sudarsanam, S. The protein kinase complement of the human genome. Science 298, 1912–1934 (2002).
Mellor, H. & Parker, P. J. The extended protein kinase C superfamily. Biochem. J. 332, 281–292 (1998).
Levin, D. E., Fields, F. O., Kunisawa, R., Bishop, J. M. & Thorner, J. A candidate protein kinase C gene, PKC1, is required for the S. cerevisiae cell cycle. Cell 62, 213–224 (1990).
Suh, P. G. et al. Multiple roles of phosphoinositide-specific phospholipase C isozymes. BMB Rep. 41, 415–434 (2008).
Bunney, T. D. & Katan, M. PLC regulation: emerging pictures for molecular mechanisms. Trends Biochem. Sci. 36, 88–96 (2011).
Haga, R. B. & Ridley, A. J. Rho GTPases: regulation and roles in cancer cell biology. Small GTPases 7, 207–221 (2016).
Castagna, M. et al. Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters. J. Biol. Chem. 257, 7847–7851 (1982). This paper is the first to define PKC as a target for tumour promoters.
Gallegos, L. L. & Newton, A. C. Spatiotemporal dynamics of lipid signaling: protein kinase C as a paradigm. IUBMB Life 60, 782–789 (2008).
Tobias, I. S. & Newton, A. C. Protein scaffolds control localized protein kinase Cζ activity. J. Biol. Chem. 291, 13809–13822 (2016).
Hong, Y. aPKC: the kinase that phosphorylates cell polarity. F1000Res 7, 903 (2018).
Amano, M. et al. Identification of a putative target for Rho as the serine–threonine kinase protein kinase N. Science 271, 648–650 (1996).
Bauer, A. F. et al. Regulation of protein kinase C-related protein kinase 2 (PRK2) by an intermolecular PRK2–PRK2 interaction mediated by its N-terminal domain. J. Biol. Chem. 287, 20590–20602 (2012).
Jaken, S. & Parker, P. J. Protein kinase C binding partners. Bioessays 22, 245–254 (2000).
Schechtman, D. & Mochly-Rosen, D. Adaptor proteins in protein kinase C-mediated signal transduction. Oncogene 20, 6339–6347 (2001).
Saurin, A. T. et al. The regulated assembly of a PKCε complex controls the completion of cytokinesis. Nat. Cell Biol. 10, 891–901 (2008).
Schonwasser, D. C., Marais, R. M., Marshall, C. J. & Parker, P. J. Activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway by conventional, novel, and atypical protein kinase C isotypes. Mol. Cell Biol. 18, 790–798 (1998).
Le Good, J. A. et al. Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1. Science 281, 2042–2045 (1998).
Chou, M. M. et al. Regulation of protein kinase Cζ by PI3-kinase and PDK-1. Curr. Biol. 8, 1069–1077 (1998).
Dutil, E. M., Toker, A. & Newton, A. C. Regulation of conventional protein kinase C isozymes by phosphoinositide-dependent kinase 1 (PDK-1). Curr. Biol. 8, 1366–1375 (1998).
Cameron, A. J., Linch, M. D., Saurin, A. T., Escribano, C. & Parker, P. J. mTORC2 targets AGC kinases through Sin1-dependent recruitment. Biochem. J. 439, 287–297 (2011).
Newton, A. C. Protein kinase C as a tumor suppressor. Semin. Cancer Biol. 48, 18–26 (2018).
Cameron, A. J., Escribano, C., Saurin, A. T., Kostelecky, B. & Parker, P. J. PKC maturation is promoted by nucleotide pocket occupation independently of intrinsic kinase activity. Nat. Struct. Mol. Biol. 16, 624–630 (2009). This paper demonstrates that in cells the occupation of the nucleotide binding pocket of PKC with nucleotides or inhibitors has a profound impact on its priming phosphorylation state.
Gould, C. M. et al. Active site inhibitors protect protein kinase C from dephosphorylation and stabilize its mature form. J. Biol. Chem. 286, 28922–28930 (2011).
Srivastava, J., Goris, J., Dilworth, S. M. & Parker, P. J. Dephosphorylation of PKCδ by protein phosphatase 2Ac and its inhibition by nucleotides. FEBS Lett. 516, 265–269 (2002).
Torbett, N. E., Casamassima, A. & Parker, P. J. Hyperosmotic-induced protein kinase N 1 activation in a vesicular compartment is dependent upon Rac1 and 3-phosphoinositide-dependent kinase 1. J. Biol. Chem. 278, 32344–32351 (2003).
Newton, A. C. Protein kinase C: poised to signal. Am. J. Physiol. Endocrinol. Metab. 298, E395–E402 (2010).
Balendran, A., Hare, G. R., Kieloch, A., Williams, M. R. & Alessi, D. R. Further evidence that 3-phosphoinositide-dependent protein kinase-1 (PDK1) is required for the stability and phosphorylation of protein kinase C (PKC) isoforms. FEBS Lett. 484, 217–223 (2000).
Cameron, A. J. et al. Protein kinases, from B to C. Biochem. Soc. Trans. 35, 1013–1017 (2007).
Nishikawa, K., Toker, A., Johannes, F. J., Songyang, Z. & Cantley, L. C. Determination of the specific substrate sequence motifs of protein kinase C isozymes. J. Biol. Chem. 272, 952–960 (1997).
Betson, M. & Settleman, J. A rho-binding protein kinase C-like activity is required for the function of protein kinase N in Drosophila development. Genetics 176, 2201–2212 (2007).
Lachmann, S. et al. Regulatory domain selectivity in the cell-type specific PKN-dependence of cell migration. PLoS ONE 6, e21732 (2011).
Carracedo, S., Sacher, F., Brandes, G., Braun, U. & Leitges, M. Redundant role of protein kinase Cδ and epsilon during mouse embryonic development. PLoS ONE 9, e103686 (2014).
Linch, M. et al. A cancer-associated mutation in atypical protein kinase Cι occurs in a substrate-specific recruitment motif. Sci. Signal. 6, ra82 (2013).
Pears, C. J., Kour, G., House, C., Kemp, B. E. & Parker, P. J. Mutagenesis of the pseudosubstrate site of protein kinase C leads to activation. Eur. J. Biochem. 194, 89–94 (1990).
Antal, C. E., Callender, J. A., Kornev, A. P., Taylor, S. S. & Newton, A. C. Intramolecular C2 domain-mediated autoinhibition of protein kinase C βII. Cell Rep. 12, 1252–1260 (2015).
Stabel, S., Rodriguez-Pena, A., Young, S., Rozengurt, E. & Parker, P. J. Quantitation of protein kinase C by immunoblot—expression in different cell lines and response to phorbol esters. J. Cell Physiol. 130, 111–117 (1987).
Lee, H. W., Smith, L., Pettit, G. R. & Smith, J. B. Bryostatin 1 and phorbol ester down-modulate protein kinase C-α and -ε via the ubiquitin/proteasome pathway in human fibroblasts. Mol. Pharmacol. 51, 439–447 (1997).
Lee, H. W., Smith, L., Pettit, G. R., Vinitsky, A. & Smith, J. B. Ubiquitination of protein kinase C-α and degradation by the proteasome. J. Biol. Chem. 271, 20973–20976 (1996).
Lu, Z. et al. Activation of protein kinase C triggers its ubiquitination and degradation. Mol. Cell Biol. 18, 839–845 (1998).
Hansra, G. et al. Multisite dephosphorylation and desensitization of conventional protein kinase C isotypes. Biochem. J. 342, 337–344 (1999).
Prevostel, C., Alice, V., Joubert, D. & Parker, P. J. Protein kinase Cα actively downregulates through caveolae-dependent traffic to an endosomal compartment. J. Cell Sci. 113, 2575–2584 (2000).
Leontieva, O. V. & Black, J. D. Identification of two distinct pathways of protein kinase Cα down-regulation in intestinal epithelial cells. J. Biol. Chem. 279, 5788–5801 (2004).
Lum, M. A., Pundt, K. E., Paluch, B. E., Black, A. R. & Black, J. D. Agonist-induced down-regulation of endogenous protein kinase Cα through an endolysosomal mechanism. J. Biol. Chem. 288, 13093–13109 (2013).
Melnikov, S. & Sagi-Eisenberg, R. Down-regulating protein kinase Cα: functional cooperation between the proteasome and the endocytic system. Cell Signal. 21, 1607–1619 (2009).
Chen, D. et al. Amplitude control of protein kinase C by RINCK, a novel E3 ubiquitin ligase. J. Biol. Chem. 282, 33776–33787 (2007).
Min, X., Zhang, X., Sun, N., Acharya, S. & Kim, K. M. Mdm2-mediated ubiquitination of PKCβII in the nucleus mediates clathrin-mediated endocytic activity. Biochem. Pharmacol. 170, 113675 (2019).
Nakamura, M., Tokunaga, F., Sakata, S. & Iwai, K. Mutual regulation of conventional protein kinase C and a ubiquitin ligase complex. Biochem. Biophys. Res. Commun. 351, 340–347 (2006).
Baffi, T. R., Van, A. N., Zhao, W., Mills, G. B. & Newton, A. C. Protein kinase C quality control by phosphatase PHLPP1 unveils loss-of-function mechanism in cancer. Mol. Cell 74, 378–392.e5 (2019).
Abrahamsen, H. et al. Peptidyl-prolyl isomerase Pin1 controls down-regulation of conventional protein kinase C isozymes. J. Biol. Chem. 287, 13262–13278 (2012).
Perander, M., Bjorkoy, G. & Johansen, T. Nuclear import and export signals enable rapid nucleocytoplasmic shuttling of the atypical protein kinase Cλ. J. Biol. Chem. 276, 13015–13024 (2001).
Ivaska, J., Bosca, L. & Parker, P. J. PKCε is a permissive link in integrin-dependent IFN-γ signalling that facilitates JAK phosphorylation of STAT1. Nat. Cell Biol. 5, 363–369 (2003).
Pelech, S. L., Meier, K. E. & Krebs, E. G. Rapid microassay for protein kinase C translocation in Swiss 3T3 cells. Biochemistry 25, 8348–8353 (1986).
Sakai, N. et al. Direct visualization of the translocation of the γ-subspecies of protein kinase C in living cells using fusion proteins with green fluorescent protein. J. Cell Biol. 139, 1465–1476 (1997).
Gao, X. et al. Single cell analysis of PKC activation during proliferation and apoptosis induced by laser irradiation. J. Cell Physiol. 206, 441–448 (2006).
Flint, A. J., Paladini, R. D. & Koshland, D. E. Jr. Autophosphorylation of protein kinase C at three separated regions of its primary sequence. Science 249, 408–411 (1990).
Ng, T. et al. Imaging protein kinase Cα activation in cells. Science 283, 2085–2089 (1999).
Durgan, J. et al. The identification and characterization of novel PKCε phosphorylation sites provide evidence for functional cross-talk within the PKC superfamily. Biochem. J. 411, 319–331 (2008).
Durgan, J., Michael, N., Totty, N. & Parker, P. J. Novel phosphorylation site markers of protein kinase Cδ activation. FEBS Lett. 581, 3377–3381 (2007).
Rodriguez, J. et al. aPKC cycles between functionally distinct PAR protein assemblies to drive cell polarity. Dev. Cell 42, 400–415.e9 (2017).
Wodarz, A. & Näthke, I. Cell polarity in development and cancer. Nat. Cell Biol. 9, 1016–1024 (2007).
Linch, M. et al. Regulation of polarized morphogenesis by protein kinase Cι in oncogenic epithelial spheroids. Carcinogenesis 35, 396–406 (2014).
Slaga, T. J. Overview of tumor promotion in animals. Env. Health Perspect. 50, 3–14 (1983).
Hecker, E. Three stage carcinogenesis in mouse skin — recent results and present status of an advanced model system of chemical carcinogenesis. Toxicol. Pathol. 15, 245–258 (1987).
Balmain, A. Transforming ras oncogenes and multistage carcinogenesis. Br. J. Cancer 51, 1–7 (1985).
Fujiki, H., Sueoka, E. & Suganuma, M. Tumor promoters: from chemicals to inflammatory proteins. J. Cancer Res. Clin. Oncol. 139, 1603–1614 (2013).
Nishizuka, Y. The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature 308, 693–698 (1984).
Ono, Y. et al. Phorbol ester binding to protein kinase C requires a cysteine-rich zinc-finger-like sequence. Proc. Natl Acad. Sci. USA 86, 4868–4871 (1989). This paper is the first demonstration that the cysteine-rich C1 domains are bound by phorbol esters, impacting our definition of this entire class of responsive proteins.
Fujiki, H. et al. Activation of calcium-activated, phospholipid-dependent protein kinase (protein kinase C) by new classes of tumor promoters: teleocidin and debromoaplysiatoxin. Biochem. Biophys. Res. Commun. 120, 339–343 (1984).
Miyake, R. et al. Activation of protein kinase C by non-phorbol tumor promoter, mezerein. Biochem. Biophys. Res. Commun. 121, 649–656 (1984).
Arcoleo, J. P. & Weinstein, I. B. Activation of protein kinase C by tumor promoting phorbol esters, teleocidin and aplysiatoxin in the absence of added calcium. Carcinogenesis 6, 213–217 (1985).
Thastrup, O., Cullen, P. J., Drobak, B. K., Hanley, M. R. & Dawson, A. P. Thapsigargin, a tumor promoter, discharges intracellular Ca2+ stores by specific inhibition of the endoplasmic reticulum Ca2+-ATPase. Proc. Natl Acad. Sci. USA 87, 2466–2470 (1990).
Haystead, T. A. et al. Effects of the tumour promoter okadaic acid on intracellular protein phosphorylation and metabolism. Nature 337, 78–81 (1989).
Manzow, S., Richter, K. H., Stempka, L., Fürstenberger, G. & Marks, F. Evidence against a role of general protein kinase C downregulation in skin tumor promotion. Int. J. Cancer 85, 503–507 (2000).
Arnott, C. H. et al. Tumour necrosis factor-α mediates tumour promotion via a PKCα- and AP-1-dependent pathway. Oncogene 21, 4728–4738 (2002).
Kazanietz, M. G. Novel “nonkinase” phorbol ester receptors: the C1 domain connection. Mol. Pharmacol. 61, 759–767 (2002).
Soloff, R. S., Katayama, C., Lin, M. Y., Feramisco, J. R. & Hedrick, S. M. Targeted deletion of protein kinase Cλ reveals a distribution of functions between the two atypical protein kinase C isoforms. J. Immunol. 173, 3250–3260 (2004).
Quetier, I. et al. Knockout of the PKN family of rho effector kinases reveals a non-redundant role for PKN2 in developmental mesoderm expansion. Cell Rep. 14, 440–448 (2016).
Oster, H. & Leitges, M. Protein kinase Cα but not PKCζ suppresses intestinal tumor formation in ApcMin/+ mice. Cancer Res. 66, 6955–6963 (2006). This paper presents direct evidence that, in the ApcMin/+ mouse model of colorectal cancer, PKCα suppresses tumour progression.
Cataisson, C. et al. Activation of cutaneous protein kinase Cα induces keratinocyte apoptosis and intraepidermal inflammation by independent signaling pathways. J. Immunol. 171, 2703–2713 (2003).
Wang, H. Q. & Smart, R. C. Overexpression of protein kinase C-α in the epidermis of transgenic mice results in striking alterations in phorbol ester-induced inflammation and COX-2, MIP-2 and TNF-α expression but not tumor promotion. J. Cell Sci. 112, 3497–3506 (1999).
Hara, T. et al. Deficiency of protein kinase Cα in mice results in impairment of epidermal hyperplasia and enhancement of tumor formation in two-stage skin carcinogenesis. Cancer Res. 65, 7356–7362 (2005).
Reddig, P. J. et al. Transgenic mice overexpressing protein kinase Cδ in the epidermis are resistant to skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res. 59, 5710–5718 (1999).
Aziz, M. H., Wheeler, D. L., Bhamb, B. & Verma, A. K. Protein kinase Cδ overexpressing transgenic mice are resistant to chemically but not to UV radiation-induced development of squamous cell carcinomas: a possible link to specific cytokines and cyclooxygenase-2. Cancer Res. 66, 713–722 (2006).
Miyamoto, A. et al. Increased proliferation of B cells and auto-immunity in mice lacking protein kinase Cδ. Nature 416, 865–869 (2002). This paper presents a description of B cell lymphoproliferative disorder in the PKCδ knockout mouse.
Mecklenbrauker, I., Saijo, K., Zheng, N. Y., Leitges, M. & Tarakhovsky, A. Protein kinase Cδ controls self-antigen-induced B-cell tolerance. Nature 416, 860–865 (2002).
Kuehn, H. S. et al. Loss-of-function of the protein kinase Cδ (PKCδ) causes a B-cell lymphoproliferative syndrome in humans. Blood 121, 3117–3125 (2013).
Allen-Petersen, B. L., Carter, C. J., Ohm, A. M. & Reyland, M. E. Protein kinase Cδ is required for ErbB2-driven mammary gland tumorigenesis and negatively correlates with prognosis in human breast cancer. Oncogene 33, 1306–1315 (2014).
Symonds, J. M. et al. Protein kinase Cδ is a downstream effector of oncogenic K-ras in lung tumors. Cancer Res. 71, 2087–2097 (2011).
Leitges, M. et al. Immunodeficiency in protein kinase Cβ-deficient mice. Science 273, 788–791 (1996).
Tsui, C. et al. Protein kinase C-β dictates B cell fate by regulating mitochondrial remodeling, metabolic reprogramming, and heme biosynthesis. Immunity 48, 1144–1159.e5 (2018).
Pfeifhofer, C. et al. Defective IgG2a/2b class switching in PKCα–/– mice. J. Immunol. 176, 6004–6011 (2006).
Martini, S. et al. PKCε promotes human TH17 differentiation: implications in the pathophysiology of psoriasis. Eur. J. Immunol. 48, 644–654 (2018).
Castrillo, A. et al. Protein kinase Cε is required for macrophage activation and defense against bacterial infection. J. Exp. Med. 194, 1231–1242 (2001).
Pfeifhofer, C. et al. Protein kinase Cθ affects Ca2+ mobilization and NFAT cell activation in primary mouse T cells. J. Exp. Med. 197, 1525–1535 (2003).
Thuille, N. et al. Loss-of-function phenotype of a PKCθT219A knockin mouse strain. Cell Commun. Signal. 17, 141 (2019).
He, X. et al. Targeting PKC in human T cells using sotrastaurin (AEB071) preserves regulatory T cells and prevents IL-17 production. J. Invest. Dermatol. 134, 975–983 (2014).
Kwon, M. J., Ma, J., Ding, Y., Wang, R. & Sun, Z. Protein kinase C-θ promotes TH17 differentiation via upregulation of Stat3. J. Immunol. 188, 5887–5897 (2012).
Kong, K. F. et al. Protein kinase C-η controls CTLA-4-mediated regulatory T cell function. Nat. Immunol. 15, 465–472 (2014).
Chida, K. et al. Disruption of protein kinase Cη results in impairment of wound healing and enhancement of tumor formation in mouse skin carcinogenesis. Cancer Res. 63, 2404–2408 (2003).
Park, D. W. et al. TLR2 stimulates ABCA1 expression via PKC-η and PLD2 pathway. Biochem. Biophys. Res. Commun. 430, 933–937 (2013).
Fu, G. et al. Protein kinase Cη is required for T cell activation and homeostatic proliferation. Sci. Signal. 4, ra84 (2011).
Wallace, J. A. et al. Protein kinase Cβ in the tumor microenvironment promotes mammary tumorigenesis. Front. Oncol. 4, 87 (2014).
Park, E. et al. Stromal cell protein kinase C-β inhibition enhances chemosensitivity in B cell malignancies and overcomes drug resistance. Sci. Transl Med. https://doi.org/10.1126/scitranslmed.aax9340 (2020).
Mukai, H. et al. PKN3 is the major regulator of angiogenesis and tumor metastasis in mice. Sci. Rep. 6, 18979 (2016).
Hattori, Y., Kikuchi, T., Nakamura, M., Ozaki, K. I. & Onishi, H. Therapeutic effects of protein kinase N3 small interfering RNA and doxorubicin combination therapy on liver and lung metastases. Oncol. Lett. 14, 5157–5166 (2017).
Leenders, F. et al. PKN3 is required for malignant prostate cell growth downstream of activated PI3-kinase. EMBO J. 23, 3303–3313 (2004).
Kraft, A. S., Smith, J. B. & Berkow, R. L. Bryostatin, an activator of the calcium phospholipid-dependent protein kinase, blocks phorbol ester-induced differentiation of human promyelocytic leukemia cells HL-60. Proc. Natl Acad. Sci. USA 83, 1334–1338 (1986).
Mackanos, E. A., Pettit, G. R. & Ramsdell, J. S. Bryostatins selectively regulate protein kinase C-mediated effects on GH4 cell proliferation. J. Biol. Chem. 266, 11205–11212 (1991).
Szallasi, Z., Smith, C. B., Pettit, G. R. & Blumberg, P. M. Differential regulation of protein kinase C isozymes by bryostatin 1 and phorbol 12-myristate 13-acetate in NIH 3T3 fibroblasts. J. Biol. Chem. 269, 2118–2124 (1994).
Hennings, H. et al. Bryostatin 1, an activator of protein kinase C, inhibits tumor promotion by phorbol esters in SENCAR mouse skin. Carcinogenesis 8, 1343–1346 (1987). This paper demonstrates that despite its shared ability to activate PKC, bryostatin 1 inhibits phorbol ester-promoted tumour formation.
Boyle, G. M. et al. Intra-lesional injection of the novel PKC activator EBC-46 rapidly ablates tumors in mouse models. PLoS ONE 9, e108887 (2014). This paper presents evidence that the PKC-activating epoxytigliane EBC-46 can trigger tumour regression on intratumoural injection.
Miller, J. et al. Dose characterization of the investigational anticancer drug tigilanol tiglate (EBC-46) in the local treatment of canine mast cell tumors. Front. Vet. Sci. 6, 106 (2019).
Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002).
Antal, C. E. et al. Cancer-associated protein kinase C mutations reveal kinase’s role as tumor suppressor. Cell 160, 489–502 (2015).
Bangham, C. R. & Ratner, L. How does HTLV-1 cause adult T-cell leukaemia/lymphoma (ATL)? Curr. Opin. Virol. 14, 93–100 (2015).
Kataoka, K. et al. Integrated molecular analysis of adult T cell leukemia/lymphoma. Nat. Genet. 47, 1304–1315 (2015). This paper presents a comprehensive description of the mutational landscape of ATLL and the identification of PKCβ as a frequent mutation target.
Wang, C., Shang, Y., Yu, J. & Zhang, M. Substrate recognition mechanism of atypical protein kinase Cs revealed by the structure of PKCι in complex with a substrate peptide from Par-3. Structure 20, 791–801 (2012).
Shinohara, H. et al. PKCβ regulates BCR-mediated IKK activation by facilitating the interaction between TAK1 and CARMA1. J. Exp. Med. 202, 1423–1431 (2005).
Soriano, E. V. et al. aPKC inhibition by Par3 CR3 flanking regions controls substrate access and underpins apical-junctional polarization. Dev. Cell 38, 384–398 (2016).
Linch, M. Protein Kinase Cι in Mammalian Cell Polarity and Cancer. PhD thesis, Univ. College London (2012).
Shimoyama, M. Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984–87). Br. J. Haematol. 79, 428–437 (1991).
Brat, D. J. et al. Third ventricular chordoid glioma: a distinct clinicopathologic entity. J. Neuropathol. Exp. Neurol. 57, 283–290 (1998).
Morais, B. A., Menendez, D. F., Medeiros, R. S., Teixeira, M. J. & Lepski, G. A. Chordoid glioma: case report and review of the literature. Int. J. Surg. Case Rep. 7c, 168–171 (2015).
Rosenberg, S. et al. A recurrent point mutation in PRKCA is a hallmark of chordoid gliomas. Nat. Commun. 9, 2371 (2018).
Goode, B. et al. A recurrent kinase domain mutation in PRKCA defines chordoid glioma of the third ventricle. Nat. Commun. 9, 810 (2018). Together with Rosenberg et al. (2018), this paper demonstrates a fully penetrant mutation in PKCα in chordoid gliomas.
Madhusudan et al. cAMP-dependent protein kinase: crystallographic insights into substrate recognition and phosphotransfer. Protein Sci. 3, 176–187 (1994).
Leitges, M. et al. Knockout of PKCα enhances insulin signaling through PI3K. Mol. Endocrinol. 16, 847–858 (2002).
Cameron, A. J., Procyk, K. J., Leitges, M. & Parker, P. J. PKCα protein but not kinase activity is critical for glioma cell proliferation and survival. Int. J. Cancer 123, 769–779 (2008).
Black, A. R. & Black, J. D. Protein kinase C signaling and cell cycle regulation. Front. Immunol. 3, 423 (2012).
Poli, A., Mongiorgi, S., Cocco, L. & Follo, M. Y. Protein kinase C involvement in cell cycle modulation. Biochem. Soc. Trans. 42, 1471–1476 (2014).
Gao, Q. et al. PKCα affects cell cycle progression and proliferation in human RPE cells through the downregulation of p27kip1. Mol. Vis. 15, 2683–2695 (2009).
Kashiwagi, M. et al. PKCη associates with cyclin E/cdk2/p21 complex, phosphorylates p21 and inhibits cdk2 kinase in keratinocytes. Oncogene 19, 6334–6341 (2000).
Mall, M. et al. Mitotic lamin disassembly is triggered by lipid-mediated signaling. J. Cell Biol. 198, 981–990 (2012).
Edens, L. J., Dilsaver, M. R. & Levy, D. L. PKC-mediated phosphorylation of nuclear lamins at a single serine residue regulates interphase nuclear size in Xenopus and mammalian cells. Mol. Biol. Cell 28, 1389–1399 (2017).
Goss, V. L. et al. Identification of nuclear βII protein kinase C as a mitotic lamin kinase. J. Biol. Chem. 269, 19074–19080 (1994).
Larijani, B. et al. Principle of duality in phospholipids: regulators of membrane morphology and dynamics. Biochem. Soc. Trans. 42, 1335–1342 (2014).
Brownlow, N., Pike, T., Zicha, D., Collinson, L. & Parker, P. J. Mitotic catenation is monitored and resolved by a PKCε-regulated pathway. Nat. Commun. 5, 5685 (2014). This paper defines, for the first time, the cell cycle dependence on PKCε in cells with a dysfunctional Topo2-dependent G2 arrest.
Downes, C. S. et al. A topoisomerase II-dependent G2 cycle checkpoint in mammalian cells. Nature 372, 467–470 (1994).
Pandey, N. et al. Topoisomerase II SUMOylation activates a metaphase checkpoint via Haspin and Aurora B kinases. J. Cell Biol. https://doi.org/10.1083/jcb.201807189 (2019).
Deiss, K. et al. A genome-wide RNAi screen identifies the SMC5/6 complex as a non-redundant regulator of a Topo2a-dependent G2 arrest. Nucleic Acids Res. 47, 2906–2921 (2019). This paper demonstrates that a genome-wide screen for genes engaged in the Topo2-dependent G2 arrest provides molecular insight into the context of PKCε dependence.
Martini, S. et al. PKCε controls mitotic progression by regulating centrosome migration and mitotic spindle assembly. Mol. Cancer Res. 16, 3–15 (2018).
Kelly, J. R. et al. The Aurora B specificity switch is required to protect from non-disjunction at the metaphase/anaphase transition. Nat. Commun. 11, 1396 (2020).
Pike, T., Brownlow, N., Kjaer, S., Carlton, J. & Parker, P. J. PKCε switches Aurora B specificity to exit the abscission checkpoint. Nat. Commun. 7, 13853 (2016).
Chen, D., Purohit, A., Halilovic, E., Doxsey, S. J. & Newton, A. C. Centrosomal anchoring of protein kinase C βII by pericentrin controls microtubule organization, spindle function, and cytokinesis. J. Biol. Chem. 279, 4829–4839 (2004).
Kawamoto, S. & Hidaka, H. 1-(5-Isoquinolinesulfonyl)-2-methylpiperazine (H-7) is a selective inhibitor of protein kinase C in rabbit platelets. Biochem. Biophys. Res. Commun. 125, 258–264 (1984).
Tamaoki, T. et al. Staurosporine, a potent inhibitor of phospholipid/Ca++ dependent protein kinase. Biochem. Biophys. Res. Commun. 135, 397–402 (1986).
Toullec, D. et al. The bisindolylmaleimide GF 109203X is a potent and selective inhibitor of protein kinase C. J. Biol. Chem. 266, 15771–15781 (1991).
Mackay, H. J. & Twelves, C. J. Targeting the protein kinase C family: are we there yet? Nat. Rev. Cancer 7, 554–562 (2007).
Roffey, J. et al. Protein kinase C intervention: the state of play. Curr. Opin. Cell Biol. 21, 268–279 (2009).
Wang, H. B., Wang, X. Y., Liu, L. P., Qin, G. W. & Kang, T. G. Tigliane diterpenoids from the Euphorbiaceae and Thymelaeaceae families. Chem. Rev. 115, 2975–3011 (2015).
Raghuvanshi, R. & Bharate, S. B. Preclinical and clinical studies on bryostatins, a class of marine-derived protein kinase C modulators: a mini-review. Curr. Top. Med. Chem. 20, 1124–1135 (2020).
Saavedra, A. et al. Chelerythrine promotes Ca2+-dependent calpain activation in neuronal cells in a PKC-independent manner. Biochim. Biophys. Acta Gen. Subj. 1861, 922–935 (2017).
Dar, M. I. et al. Rottlerin is a pan phosphodiesterase inhibitor and can induce neurodifferentiation in IMR-32 human neuroblastoma cells. Eur. J. Pharmacol. 857, 172448 (2019).
Meyer, T. et al. A derivative of staurosporine (CGP 41 251) shows selectivity for protein kinase C inhibition and in vitro anti-proliferative as well as in vivo anti-tumor activity. Int. J. Cancer 43, 851–856 (1989).
Kayser, S., Levis, M. J. & Schlenk, R. F. Midostaurin treatment in FLT3-mutated acute myeloid leukemia and systemic mastocytosis. Expert. Rev. Clin. Pharmacol. 10, 1177–1189 (2017).
Graves, P. R. et al. The Chk1 protein kinase and the Cdc25C regulatory pathways are targets of the anticancer agent UCN-01. J. Biol. Chem. 275, 5600–5605 (2000).
Bourhill, T., Narendran, A. & Johnston, R. N. Enzastaurin: a lesson in drug development. Crit. Rev. Oncol. Hematol. 112, 72–79 (2017).
Carducci, M. A. et al. Phase I dose escalation and pharmacokinetic study of enzastaurin, an oral protein kinase Cβ inhibitor, in patients with advanced cancer. J. Clin. Oncol. 24, 4092–4099 (2006).
Clamp, A. & Jayson, G. C. The clinical development of the bryostatins. Anticancer Drugs 13, 673–683 (2002).
Ku, G. Y. et al. Phase II trial of sequential paclitaxel and 1 h infusion of bryostatin-1 in patients with advanced esophageal cancer. Cancer Chemother. Pharmacol. 62, 875–880 (2008).
Panizza, B. J. et al. Phase I dose-escalation study to determine the safety, tolerability, preliminary efficacy and pharmacokinetics of an intratumoral injection of tigilanol tiglate (EBC-46). EBioMedicine 50, 433–441 (2019).
Decatur, C. L. et al. Driver mutations in uveal melanoma: associations with gene expression profile and patient outcomes. JAMA Ophthalmol. 134, 728–733 (2016).
Gresset, A., Sondek, J. & Harden, T. K. The phospholipase C isozymes and their regulation. Subcell. Biochem. 58, 61–94 (2012).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02273219?term=aeb071&draw=2&rank=1 (2018).
Skvara, H. et al. The PKC inhibitor AEB071 may be a therapeutic option for psoriasis. J. Clin. Invest. 118, 3151–3159 (2008).
Piperno-Neumann, S. et al. Genomic profiling of metastatic uveal melanoma and clinical results of a phase I study of the protein kinase C inhibitor AEB071. Mol. Cancer Ther. https://doi.org/10.1158/1535-7163.Mct-19-0098 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03947385 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02601378 (2020).
Kapiteijn, E. et al. Abstract CT068: a phase I trial of LXS196, a novel PKC inhibitor for metastatic uveal melanoma. Cancer Res. 79, CT068–CT068 (2019).
Robertson, M. J. et al. Phase II study of enzastaurin, a protein kinase Cβ inhibitor, in patients with relapsed or refractory diffuse large B-cell lymphoma. J. Clin. Oncol. 25, 1741–1746 (2007).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03263026 (2020).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03492125 (2019).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01737502 (2020).
Erdogan, E. et al. Aurothiomalate inhibits transformed growth by targeting the PB1 domain of protein kinase Cι. J. Biol. Chem. 281, 28450–28459 (2006).
Suzuki, A. & Ohno, S. The PAR–aPKC system: lessons in polarity. J. Cell Sci. 119, 979–987 (2006).
Drummond, M. L. & Prehoda, K. E. Molecular control of atypical protein kinase C: tipping the balance between self-renewal and differentiation. J. Mol. Biol. 428, 1455–1464 (2016).
Etienne-Manneville, S. From signaling pathways to microtubule dynamics: the key players. Curr. Opin. Cell Biol. 22, 104–111 (2010).
Murray, N. R. & Fields, A. P. Atypical protein kinase Cι protects human leukemia cells against drug-induced apoptosis. J. Biol. Chem. 272, 27521–27524 (1997).
Weichert, W., Gekeler, V., Denkert, C., Dietel, M. & Hauptmann, S. Protein kinase C isoform expression in ovarian carcinoma correlates with indicators of poor prognosis. Int. J. Oncol. 23, 633–639 (2003).
Zhang, L. et al. Integrative genomic analysis of protein kinase C (PKC) family identifies PKCι as a biomarker and potential oncogene in ovarian carcinoma. Cancer Res. 66, 4627–4635 (2006).
Eder, A. M. et al. Atypical PKCι contributes to poor prognosis through loss of apical-basal polarity and cyclin E overexpression in ovarian cancer. Proc. Natl Acad. Sci. USA 102, 12519–12524 (2005).
Regala, R. P. et al. Atypical protein kinase Cι is an oncogene in human non-small cell lung cancer. Cancer Res. 65, 8905–8911 (2005).
Li, Q. et al. Correlation of aPKC-ι and E-cadherin expression with invasion and prognosis of cholangiocarcinoma. Hepatob. Pancreat. Dis. Int. 7, 70–75 (2008).
Yang, Y. L. et al. Amplification of PRKCI, located in 3q26, is associated with lymph node metastasis in esophageal squamous cell carcinoma. Genes Chromosomes Cancer 47, 127–136 (2008).
Scotti, M. L., Bamlet, W. R., Smyrk, T. C., Fields, A. P. & Murray, N. R. Protein kinase Cι is required for pancreatic cancer cell transformed growth and tumorigenesis. Cancer Res. 70, 2064–2074 (2010).
Ishiguro, H. et al. aPKCλ/ι promotes growth of prostate cancer cells in an autocrine manner through transcriptional activation of interleukin-6. Proc. Natl Acad. Sci. USA 106, 16369–16374 (2009).
Ma, L. et al. Control of nutrient stress-induced metabolic reprogramming by PKCζ in tumorigenesis. Cell 152, 599–611 (2013).
Reina-Campos, M., Diaz-Meco, M. T. & Moscat, J. The dual roles of the atypical protein kinase Cs in cancer. Cancer Cell 36, 218–235 (2019). This paper presents a detailed commentary on aPKC in cancer models.
Reina-Campos, M. et al. Increased serine and one-carbon pathway metabolism by PKCλ/ι deficiency promotes neuroendocrine prostate cancer. Cancer Cell 35, 385–400.e9 (2019).
Nakanishi, Y. et al. Simultaneous loss of both atypical protein kinase C genes in the intestinal epithelium drives serrated intestinal cancer by impairing immunosurveillance. Immunity 49, 1132–1147.e7 (2018).
Huang, X. et al. An atypical protein kinase C (PKCζ) plays a critical role in lipopolysaccharide-activated NF-κB in human peripheral blood monocytes and macrophages. J. Immunol. 182, 5810–5815 (2009).
Murray, N. R. et al. Protein kinase Cι is required for Ras transformation and colon carcinogenesis in vivo. J. Cell Biol. 164, 797–802 (2004).
Regala, R. P. et al. Atypical protein kinase Cι is required for bronchioalveolar stem cell expansion and lung tumorigenesis. Cancer Res. 69, 7603–7611 (2009). This paper demonstrates that knockout of PKCι suppresses lung tumour formation at switch on of G12D-mutant K-Ras expression.
The authors thank A. Fields and M. Reyland for commenting on the manuscript. They also acknowledge support from the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001130), the UK Medical Research Council (FC001130) and the Wellcome Trust (FC001130). M.L. is supported by the National Institute for Health Research, the University College London Hospitals Biomedical Research Centre (no grant numbers apply).
The authors declare no competing interests.
Peer review information
Nature Reviews Cancer thanks M.G. Kazanietz, M. Leitges and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
FDA orphan status was designated to bryostatin: https://www.accessdata.fda.gov/scripts/opdlisting/oopd/listResult.cfm
PKC412 in acute myeloid leukaemia: https://clinicaltrials.gov/ct2/results?cond = AML&term = PKC412
PKC412 in myelodysplastic syndrome: https://clinicaltrials.gov/ct2/results?cond = MDS&term = PKC412
Tigilanol tiglate: https://www.ema.europa.eu/en/medicines/veterinary/EPAR/stelfonta
(DAG). A neutral lipid component of membranes, serving in the biosynthesis of more complex lipids and as a signalling lipid.
Used in a generic manner to indicate a particular protein conformation.
- MMTV-ERBB2 transformation model
A transgenic mouse model with expression of the receptor tyrosine kinase ERBB2 under the control of the mammary gland selective MMTV promoter.
Trace bioactive cyclic polyketides first identified in marine bryozoan Bugula neritina; they likely originate from the symbiont B. neritina.
Bioactive compounds originally identified in the kernels of Fontainea picrosperma fruits and related to phorbol esters (tigliane family of diterpenes).
- Private mutations
Those rare mutations that appear only once in cancer genomes, that is, are private to that patient.
- Topoisomerase 2α
(Topo2α). One of two genes in mammals that catalyse the resolution of intertwined, catenated DNA, through double-strand cutting, strand passage and religation reactions.
One of the components of the chromosome passenger complex (CPC), alongside INCENP and survivin, regulating the localization and activity of the co-associated Aurora B, which completes the CPC.
About this article
Cite this article
Parker, P.J., Brown, S.J., Calleja, V. et al. Equivocal, explicit and emergent actions of PKC isoforms in cancer. Nat Rev Cancer 21, 51–63 (2021). https://doi.org/10.1038/s41568-020-00310-4
PKCα is a Potentially Useful Marker for Planning Individualized Radiotherapy for Nasopharyngeal Carcinoma
Cancer Management and Research (2021)
Biochemical Pharmacology (2021)