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Atlas of Genetics and Cytogenetics in Oncology and Haematology INIST-CNRS OPEN ACCESS JOURNAL Gene Section Review PRKCI (protein kinase C, iota) Verline Justilien, Alan P Fields Department of Cancer Biology, Mayo Clinic College of Medicine, Jacksonville, Florida, 32224 USA (VJ, APF) Published in Atlas Database: June 2012 Online updated version : http://AtlasGeneticsOncology.org/Genes/PRKCIID41857ch3q26.html DOI: 10.4267/2042/48364 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity Protein Other names: DXS1179E: nPKC-iota: PKCI HGNC (Hugo): PRKCI Location: 3q26.2 Local order The PRKCI gene is located between the polyhomeotic homolog 3 gene in centromeric position and the SKIlike oncogene in telomeric position (according to GeneLoc). Description PKCι consist of 596 amino acids and has a molecular mass of 68262 Da. PKCι is a member of the PKCs, a diverse family of lipid dependent serine/threonine kinases. PKCι activity can be regulated by lipid second messengers (ceramide, phosphatidylinositol 3,4,5-P3, and phosphatidic acid), phosphoinositide-dependent kinase (PDK1), tyrosine phosphorylation and specific protein-protein interactions. The PB1 domain within the N-terminal regulatory domain mediates protein-protein interactions between PKCι and other PB1 domain containing proteins such as ZIP/p62 (Hirano et al., 2004; Puls et al., 1997), Par-6 (partitioning-defective 6) (Joberty et al., 2000; Lin et al., 2000; Noda et al., 2001; Qiu et al., 2000) and MEK5 (MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase 5) (Diaz-Meco and Moscat, 2001; Hirano et al., 2004). In the inactive state, the PKCι PS is positioned in the substrate binding cavity in the kinase domain and is displaced upon PKCι activation. DNA/RNA Description The PRKCI gene is composed of 18 exons and spans 83618 bases on the plus strand. Transcription The PRKCI transcript (NM_002740) contains 4884 bases and the open reading frame spans from 239 to 2029. Pseudogene There is a single exon pseudogene mapped on chromosome X. Location sequence of PRKCI on Chromosome 3. PRKCI gene is indicated by red arrow. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(12) 913 PRKCI (protein kinase C, iota) Justilien V, Fields AP Exon-intron structure of the PRKCI gene. Blue vertical bars correspond to exons, green bar represents 5'UTR and orange 3'UTR. Schematic diagram showing the domain structure of PKCι. PB-1 Phox-Bem1; PS: auto-inhibitory pseudosubstrate sequence. Phosphatidylserine binds the C1 domain to anchor PKCι to the membrane. The PKCι catalytic domain is subdivided into the C3 and C4 domains that mediate ATP-binding and substrate binding. (Yang et al., 2008) and ovarian (Eder et al., 2005; Zhang et al., 2006) cancers. A P118L mutation was found in a metastatic melanoma sample (Greenman et al., 2007). Expression Implicated in PKCι is widely expressed with varying levels in different tissues (Selbie et al., 1993). Various cancers Localisation Note PKCι overexpression has been observed in numerous human cancers including cancers of the lung (Regala et al., 2005b), pancreas (Scotti et al., 2010), stomach (Takagawa et al., 2010), colon (Murray et al., 2004), esophagus (Yang et al., 2008), liver (Du et al., 2009), bile duct (Li et al., 2008), breast (Kojima et al., 2008), ovary (Weichert et al., 2003; Eder et al., 2005; Zhang et al., 2006), prostate (Ishiguro et al., 2009), and brain (Patel et al., 2008). PKCι is itself an oncogene, which appears to be activated through tumor-specific overexpression. In addition, however, PKCι is activated downstream of other oncogenes including oncogenic Ras, Bcr-Abl and Src. PKCι is mainly expressed in the cytoplasm. PKCι is translocated to the cell membrane in response to second messengers and colocalizes with p62/ZIP in lysosometargeted endosomes (Sanchez et al., 1998). Src phosphorylation leads to translocation of PKCι into the nucleus (White et al., 2002) where it forms a complex with Cdk7 (Win and Acevedo-Duncan, 2008). Function PKCι is a lipid-dependent, serine/threonine kinase. PKCι participates a number of signaling pathways that regulate cell survival (Sanz et al., 1999; Wooten et al., 1999; Xie et al., 2000), differentiation (Wooten et al., 2000), polarity (Joberty et al., 2000), and microtubule dynamics in the early secretory pathway (Tisdale, 2002). Non Small Cell Lung Cancer (NSCLC) Prognosis Elevated levels of PKCι expression correlate with poor clinical outcome in NSCLC patients (Regala et al., 2005b). Cytogenetics The PRKCI gene is amplified as part of the 3q26 amplicon in NSCLC. Oncogenesis PKCι is an oncogene in NSCLC. PRKCI is amplified as part of the 3q26 amplicon in NSCLC and amplication drives PKCι overexpression in NSCLC cell lines and primary NSCLC tumours. PKCι is required for transformed (anchorage-independent) growth and invasion of human NSCLC cells (Frederick et al., 2008; Regala et al., 2005a). Disruption of the Prkci gene inhibits oncogenic Kras induced expansion and transformation of tumor-initiating, lung stem-like cells. Consequently, genetic loss of Prkci dramatically Homology PRKCI is highly evolutionarily conserved. PKCι and PKCζ exhibit 72% overall amino acid sequence homology and 86% identity within the kinase domain. PKCι shows less homology with the other PKC isoform, with less than 53% identity in the highly conserved catalytic domain (Selbie et al., 1993). Mutations Germinal No germline mutations in the PRKCI gene have been reported. Somatic The PKCι gene is amplified as part of the 3q26 amplicon in lung (Regala et al., 2005b), esophageal Atlas Genet Cytogenet Oncol Haematol. 2012; 16(12) 914 PRKCI (protein kinase C, iota) Justilien V, Fields AP et al., 2010). Analysis of human PDAC cells after orthotopic injection into the mouse pancreas revealed that PKCι-deficient tumor cells yielded significantly smaller tumors and significantly fewer metastases to the kidney, liver, diaphragm and mesentery (Scotti et al., 2010). The Rac1-MEK/ERK1/2 signaling axis is required for PKCiota-mediated transformed growth and cellular invasion of PDAC cells (Scotti et al., 2010). inhibits Kras-initiated hyperplasia and subsequent lung tumor formation in vivo. PKCι enhances resistance of NSCLC to NNK-induced apoptosis by phosphorylating the pro-apoptotic protein BAD (Jin et al., 2005). PKCι forms an oncogeneic complex with Par6 that activates a Rac1-Mek-Erk signaling axis that drives the transformed growth and invasion of NSCLC cells in vitro (Frederick et al., 2008; Regala et al., 2005a) and tumorigenicity in vivo (Regala et al., 2005a). PKCι and the oncogene ECT2 are genetically linked through coordinate gene amplification as part of the 3q26 amplicon in NSCLC tumors (Justilien and Fields, 2009). PKCι phosphorylates Ect2 and forms an oncogenic PKCι-Par6-Ect2 complex that drives NSCLC cell transformation by activating Rac1 (Justilien and Fields, 2009; Justilien et al., 2011). Expression of MMP10 is regulated through the PKCιPar6-Rac1 signaling axis and MMP10 represents a key downstream effector in PKCι mediated transformation in lung cancer cells that is required for transformed growth and invasion (Frederick et al., 2008). PKCι also regulates expression of COPB2, ELF3, RFC4, and PLS1 in primary lung adenocarcinoma (Erdogan et al., 2009). The PKCι inhibitor aurothiomalate (ATM) disrupts the PB1-PB1 domain interaction between PKCι and Par6 and inhibits PKCι-mediated Rac1 activation and blocks anchorage-independent growth of NSCLC cells in vitro and tumorigenicity in vivo (Erdogan et al., 2006; Stallings-Mann, 2006). Ovarian cancer Prognosis PKCι expression is a strong predictor of survival when combined in a multi-variate analysis with tumor cyclin E expression (Eder et al., 2005). Cytogenetics The PRKCI gene is amplified as part of the 3q26 amplicon in ovarian cancer (Eder et al., 2005). Oncogenesis PKCι is frequently overexpressed in patients with ovarian cancer (Eder et al., 2005; Weichert et al., 2003; Zhang et al., 2006). PKCι expression in ovarian cancer patients correlates with tumor stage suggesting the involvement of PKCι in tumor progression and aggressiveness (Eder et al., 2005; Weichert et al., 2003; Zhang et al., 2006). Decreased PKCι expression reduced anchorage-independent growth of ovarian cancer cells, whereas overexpression of PKCι promoted murine ovarian surface epithelium transformation (Zhang et al., 2006). Colon cancer Chronic myelogenous leukemia Oncogenesis PKCι expression is elevated in human colon tumors, AOM-induced colon tumors in mice (Murray et al., 2004) and intestinal tumors in APCMin/+ mice (Murray et al., 2009; Oster and Leitges, 2006). Expression of caPKCι in the colonic epithelium of mice led to an increase in the number of AOM-induced colon tumors, and promoted tumor progression from benign adenoma to malignant intramucosal carcinoma (Murray et al., 2004) PKCι is required for oncogenic Ras-mediated transformation of the intestinal epithelium in vitro and in vivo. PKCι is also required for the formation of intestinal tumors in APCMin/+ mice (Murray et al., 2009). Oncogenesis PKCι is highly expressed in human K562 leukemia cells and functions as a survival gene in chronic myelogenous leukemia (CML). The chimeric tyrosine kinase oncogene Bcr-Abl activates a Ras/Mek/Erk signaling pathway that stimulates PKCι expression through an Elk1 transcription factor site in the proximal promoter of PKCι (Gustafson et al., 2004). Bcr-Abl activation of PKCι is necessary and sufficient to mediate apoptotic resistance to chemotherapy in K562 CML cells (Murray and Fields, 1997). Gliomas Oncogenesis PKCι is overexpressed in glioblastoma multiforme. PKCι is required for survival and chemoresistance of glioblastoma cells. Genetic disruption of PKCι expression results in sensitization of glioblastoma cells to cisplatin (Baldwin et al., 2008). RNAi mediated depletion of PKCι also blocks the proliferative and invasive properties of glioma cell lines in vitro (Baldwin et al., 2008; Patel et al., 2008). PKCι promotes survival in glioblastoma cells through attenuation of p38 mitogen-activated protein kinase signaling that protects these cells against cytotoxicity to chemotherapeutic agents (Baldwin et al., 2008). Pancreatic cancer Prognosis PKCι overexpression predicts poor survival in pancreatic cancer patients (Scotti et al., 2010). Oncogenesis PKCι is significantly overexpressed in human pancreatic cancer. Knock down of PKCι expression using lentiviral-mediated shRNA blocked transformed (anchorage-independent) growth and invasion of human Pancreatic Ductal Adenocarcinoma (PDAC) cells (Scotti et al., 2010). Disruption of PKCι expression also blocks tumorigenicity of PDAC cell tumors injected orthotopically into the pancreas (Scotti Atlas Genet Cytogenet Oncol Haematol. 2012; 16(12) 915 PRKCI (protein kinase C, iota) Justilien V, Fields AP Esophageal cancer Noda Y, Takeya R, Ohno S, Naito S, Ito T, Sumimoto H. Human homologues of the Caenorhabditis elegans cell polarity protein PAR6 as an adaptor that links the small GTPases Rac and Cdc42 to atypical protein kinase C. Genes Cells. 2001 Feb;6(2):107-19 Cytogenetics PRKCI gene is amplified as part of the 3q26 amplicon (Yang et al., 2008). Oncogenesis PRKCI is amplified in 53% of esophageal squamous cell carcinomas (ESCC) and PKCι protein expression correlated with PRKCI gene amplification in these tumors (Yang et al., 2008). Examination of clinicopathologic features of ESCC tumors revealed a significant correlation between PRKCI expression and larger tumor size, later stage and lymph node metastasis suggesting that PRKCI overexpression is a hallmark of tumor progression and metastasis in ESCC (Yang et al., 2008). Tisdale EJ. Glyceraldehyde-3-phosphate dehydrogenase is phosphorylated by protein kinase Ciota /lambda and plays a role in microtubule dynamics in the early secretory pathway. J Biol Chem. 2002 Feb 1;277(5):3334-41 White WO, Seibenhener ML, Wooten MW. Phosphorylation of tyrosine 256 facilitates nuclear import of atypical protein kinase C. J Cell Biochem. 2002;85(1):42-53 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. 2003 Sep;23(3):633-9 References Gustafson WC, Ray S, Jamieson L, Thompson EA, Brasier AR, Fields AP. Bcr-Abl regulates protein kinase Ciota (PKCiota) transcription via an Elk1 site in the PKCiota promoter. J Biol Chem. 2004 Mar 5;279(10):9400-8 Selbie LA, Schmitz-Peiffer C, Sheng Y, Biden TJ. Molecular cloning and characterization of PKC iota, an atypical isoform of protein kinase C derived from insulin-secreting cells. J Biol Chem. 1993 Nov 15;268(32):24296-302 Hirano Y, Yoshinaga S, Ogura K, Yokochi M, Noda Y, Sumimoto H, Inagaki F. Solution structure of atypical protein kinase C PB1 domain and its mode of interaction with ZIP/p62 and MEK5. J Biol Chem. 2004 Jul 23;279(30):31883-90 Murray NR, Fields AP. Atypical protein kinase C iota protects human leukemia cells against drug-induced apoptosis. J Biol Chem. 1997 Oct 31;272(44):27521-4 Murray NR, Jamieson L, Yu W, Zhang J, Gökmen-Polar Y, Sier D, Anastasiadis P, Gatalica Z, Thompson EA, Fields AP. Protein kinase Ciota is required for Ras transformation and colon carcinogenesis in vivo. J Cell Biol. 2004 Mar 15;164(6):797-802 Puls A, Schmidt S, Grawe F, Stabel S. Interaction of protein kinase C zeta with ZIP, a novel protein kinase C-binding protein. Proc Natl Acad Sci U S A. 1997 Jun 10;94(12):6191-6 Eder AM, Sui X, Rosen DG, Nolden LK, Cheng KW, Lahad JP, Kango-Singh M, Lu KH, Warneke CL, Atkinson EN, Bedrosian I, Keyomarsi K, Kuo WL, Gray JW, Yin JC, Liu J, Halder G, Mills GB. Atypical PKCiota contributes to poor prognosis through loss of apical-basal polarity and cyclin E overexpression in ovarian cancer. Proc Natl Acad Sci U S A. 2005 Aug 30;102(35):12519-24 Sanchez P, De Carcer G, Sandoval IV, Moscat J, Diaz-Meco MT. Localization of atypical protein kinase C isoforms into lysosome-targeted endosomes through interaction with p62. Mol Cell Biol. 1998 May;18(5):3069-80 Sanz L, Sanchez P, Lallena MJ, Diaz-Meco MT, Moscat J. The interaction of p62 with RIP links the atypical PKCs to NFkappaB activation. EMBO J. 1999 Jun 1;18(11):3044-53 Jin Z, Xin M, Deng X. Survival function of protein kinase C{iota} as a novel nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1butanone-activated bad kinase. J Biol Chem. 2005 Apr 22;280(16):16045-52 Wooten MW, Seibenhener ML, Zhou G, Vandenplas ML, Tan TH. Overexpression of atypical PKC in PC12 cells enhances NGF-responsiveness and survival through an NF-kappaB dependent pathway. Cell Death Differ. 1999 Aug;6(8):753-64 Regala RP, Weems C, Jamieson L, Copland JA, Thompson EA, Fields AP. Atypical protein kinase Ciota plays a critical role in human lung cancer cell growth and tumorigenicity. J Biol Chem. 2005a Sep 2;280(35):31109-15 Joberty G, Petersen C, Gao L, Macara IG. The cell-polarity protein Par6 links Par3 and atypical protein kinase C to Cdc42. Nat Cell Biol. 2000 Aug;2(8):531-9 Regala RP, Weems C, Jamieson L, Khoor A, Edell ES, Lohse CM, Fields AP. Atypical protein kinase C iota is an oncogene in human non-small cell lung cancer. Cancer Res. 2005b Oct 1;65(19):8905-11 Lin D, Edwards AS, Fawcett JP, Mbamalu G, Scott JD, Pawson T. A mammalian PAR-3-PAR-6 complex implicated in Cdc42/Rac1 and aPKC signalling and cell polarity. Nat Cell Biol. 2000 Aug;2(8):540-7 Erdogan E, Lamark T, Stallings-Mann M, Lee Jamieson, Pellecchia M, Thompson EA, Johansen T, Fields AP. Aurothiomalate inhibits transformed growth by targeting the PB1 domain of protein kinase Ciota. J Biol Chem. 2006 Sep 22;281(38):28450-9 Qiu RG, Abo A, Steven Martin G. A human homolog of the C. elegans polarity determinant Par-6 links Rac and Cdc42 to PKCzeta signaling and cell transformation. Curr Biol. 2000 Jun 15;10(12):697-707 Oster H, Leitges M. Protein kinase C alpha but not PKCzeta suppresses intestinal tumor formation in ApcMin/+ mice. Cancer Res. 2006 Jul 15;66(14):6955-63 Wooten MW, Seibenhener ML, Neidigh KB, Vandenplas ML. Mapping of atypical protein kinase C within the nerve growth factor signaling cascade: relationship to differentiation and survival of PC12 cells. Mol Cell Biol. 2000 Jul;20(13):4494-504 Stallings-Mann M, Jamieson L, Regala RP, Weems C, Murray NR, Fields AP. A novel small-molecule inhibitor of protein kinase Ciota blocks transformed growth of non-small-cell lung cancer cells. Cancer Res. 2006 Feb 1;66(3):1767-74 Xie J, Guo Q, Zhu H, Wooten MW, Mattson MP. Protein kinase C iota protects neural cells against apoptosis induced by amyloid beta-peptide. Brain Res Mol Brain Res. 2000 Oct 20;82(1-2):107-13 Zhang L, Huang J, Yang N, Liang S, Barchetti A, Giannakakis A, Cadungog MG, O'Brien-Jenkins A, Massobrio M, Roby KF, Katsaros D, Gimotty P, Butzow R, Weber BL, Coukos G. Integrative genomic analysis of protein kinase C (PKC) family Diaz-Meco MT, Moscat J. MEK5, a new target of the atypical protein kinase C isoforms in mitogenic signaling. Mol Cell Biol. 2001 Feb;21(4):1218-27 Atlas Genet Cytogenet Oncol Haematol. 2012; 16(12) 916 PRKCI (protein kinase C, iota) Justilien V, Fields AP identifies PKCiota as a biomarker and potential oncogene in ovarian carcinoma. Cancer Res. 2006 May 1;66(9):4627-35 Amplification of PRKCI, located in 3q26, is associated with lymph node metastasis in esophageal squamous cell carcinoma. Genes Chromosomes Cancer. 2008 Feb;47(2):127-36 Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, Davies H, Teague J, Butler A, Stevens C, Edkins S, O'Meara S, Vastrik I, Schmidt EE, Avis T, Barthorpe S, Bhamra G, Buck G, Choudhury B, Clements J, Cole J, Dicks E, Forbes S, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jenkinson A, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Richardson D, Shepherd R, Small A, Tofts C, Varian J, Webb T, West S, Widaa S, Yates A, Cahill DP, Louis DN, Goldstraw P, Nicholson AG, Brasseur F, Looijenga L, Weber BL, Chiew YE, DeFazio A, Greaves MF, Green AR, Campbell P, Birney E, Easton DF, Chenevix-Trench G, Tan MH, Khoo SK, Teh BT, Yuen ST, Leung SY, Wooster R, Futreal PA, Stratton MR. Patterns of somatic mutation in human cancer genomes. Nature. 2007 Mar 8;446(7132):153-8 Du GS, Wang JM, Lu JX, Li Q, Ma CQ, Du JT, Zou SQ. Expression of P-aPKC-iota, E-cadherin, and beta-catenin related to invasion and metastasis in hepatocellular carcinoma. Ann Surg Oncol. 2009 Jun;16(6):1578-86 Erdogan E, Klee EW, Thompson EA, Fields AP. Meta-analysis of oncogenic protein kinase Ciota signaling in lung adenocarcinoma. Clin Cancer Res. 2009 Mar 1;15(5):1527-33 Ishiguro H, Akimoto K, Nagashima Y, Kojima Y, Sasaki T, Ishiguro-Imagawa Y, Nakaigawa N, Ohno S, Kubota Y, Uemura H. aPKClambda/iota promotes growth of prostate cancer cells in an autocrine manner through transcriptional activation of interleukin-6. Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16369-74 Baldwin RM, Parolin DA, Lorimer IA. Regulation of glioblastoma cell invasion by PKC iota and RhoB. Oncogene. 2008 Jun 5;27(25):3587-95 Justilien V, Fields AP. Ect2 links the PKCiota-Par6alpha complex to Rac1 activation and cellular transformation. Oncogene. 2009 Oct 15;28(41):3597-607 Frederick LA, Matthews JA, Jamieson L, Justilien V, Thompson EA, Radisky DC, Fields AP. Matrix metalloproteinase-10 is a critical effector of protein kinase Ciota-Par6alpha-mediated lung cancer. Oncogene. 2008 Aug 14;27(35):4841-53 Murray NR, Weems J, Braun U, Leitges M, Fields AP. Protein kinase C betaII and PKCiota/lambda: collaborating partners in colon cancer promotion and progression. Cancer Res. 2009 Jan 15;69(2):656-62 Kojima Y, Akimoto K, Nagashima Y, Ishiguro H, Shirai S, Chishima T, Ichikawa Y, Ishikawa T, Sasaki T, Kubota Y, Inayama Y, Aoki I, Ohno S, Shimada H. The overexpression and altered localization of the atypical protein kinase C lambda/iota in breast cancer correlates with the pathologic type of these tumors. Hum Pathol. 2008 Jun;39(6):824-31 Scotti ML, Bamlet WR, Smyrk TC, Fields AP, Murray NR. Protein kinase Ciota is required for pancreatic cancer cell transformed growth and tumorigenesis. Cancer Res. 2010 Mar 1;70(5):2064-74 Takagawa R, Akimoto K, Ichikawa Y, Akiyama H, Kojima Y, Ishiguro H, Inayama Y, Aoki I, Kunisaki C, Endo I, Nagashima Y, Ohno S. High expression of atypical protein kinase C lambda/iota in gastric cancer as a prognostic factor for recurrence. Ann Surg Oncol. 2010 Jan;17(1):81-8 Li Q, Wang JM, Liu C, Xiao BL, Lu JX, Zou SQ. Correlation of aPKC-iota and E-cadherin expression with invasion and prognosis of cholangiocarcinoma. Hepatobiliary Pancreat Dis Int. 2008 Feb;7(1):70-5 Patel R, Win H, Desai S, Patel K, Matthews JA, AcevedoDuncan M. Involvement of PKC-iota in glioma proliferation. Cell Prolif. 2008 Feb;41(1):122-35 Justilien V, Jameison L, Der CJ, Rossman KL, Fields AP. Oncogenic activity of Ect2 is regulated through protein kinase C iota-mediated phosphorylation. J Biol Chem. 2011 Mar 11;286(10):8149-57 Win HY, Acevedo-Duncan M. Atypical protein kinase C phosphorylates IKKalphabeta in transformed non-malignant and malignant prostate cell survival. Cancer Lett. 2008 Nov 8;270(2):302-11 This article should be referenced as such: Justilien V, Fields AP. PRKCI (protein kinase C, iota). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(12):913-917. Yang YL, Chu JY, Luo ML, Wu YP, Zhang Y, Feng YB, Shi ZZ, Xu X, Han YL, Cai Y, Dong JT, Zhan QM, Wu M, Wang MR. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(12) 917