KEGG   PATHWAY: ko05165
ko05165                     Pathway                                

Human papillomavirus infection
Human papillomavirus (HPV) is a non-enveloped, double-stranded DNA virus. HPV infect mucoal and cutaneous epithelium resulting in several types of pathologies, most notably, cervical cancer. All types of HPV share a common genomic structure and encode eight proteins: E1, E2, E4, E5, E6, and E7 (early) and L1 and L2 (late). It has been demonstrated that E1 and E2 are involved in viral transcription and replication. The functions of the E4 protein is not yet fully understood. E5, E6, and E7 act as oncoproteins. E5 inhibits the V-ATPase, prolonging EGFR signaling and thereby promoting cell proliferation. The expression of E6 and E7 not only inhibits the tumor suppressors p53 and Rb, but also alters additional signalling pathways. Among these pathways, PI3K/Akt signalling cascade plays a very important role in HPV-induced carcinogenesis. The L1 and L2 proteins form icosahedral capsids for progeny virion generation.
Human Diseases; Infectious disease: viral
Pathway map
ko05165  Human papillomavirus infection

H00030  Cervical cancer
K03209  wingless-type MMTV integration site family, member 1
K00182  wingless-type MMTV integration site family, member 2
K00312  wingless-type MMTV integration site family, member 3
K00408  wingless-type MMTV integration site family, member 4
K00444  wingless-type MMTV integration site family, member 5
K00445  wingless-type MMTV integration site family, member 6
K00572  wingless-type MMTV integration site family, member 7
K00714  wingless-type MMTV integration site family, member 8
K01064  wingless-type MMTV integration site family, member 9
K01357  wingless-type MMTV integration site family, member 10
K01384  wingless-type MMTV integration site family, member 11
K01558  wingless-type MMTV integration site family, member 16
K02432  frizzled 1/7
K02235  frizzled 2
K02329  frizzled 3
K02354  frizzled 4
K02375  frizzled 5/8
K02376  frizzled 6
K02842  frizzled 9/10
K02353  segment polarity protein dishevelled
K21807  HPV protein E6
K03083  glycogen synthase kinase 3 beta [EC:]
K02157  axin 1
K04385  axin 2
K02085  adenomatosis polyposis coli protein
K02105  catenin beta 1
K08957  casein kinase 1, alpha [EC:]
K11126  telomerase reverse transcriptase [EC:]
K02620  transcription factor 7
K04490  transcription factor 7-like 1
K04491  transcription factor 7-like 2
K10587  ubiquitin-protein ligase E3 A [EC:]
K05401  toll-like receptor 3
K05842  toll-like receptor adapter molecule 1
K03174  TNF receptor-associated factor 3
K07211  inhibitor of nuclear factor kappa-B kinase subunit epsilon [EC:]
K05410  TANK-binding kinase 1 [EC:]
K05411  interferon regulatory factor 3
K05415  interferon beta
K04498  E1A/CREB-binding protein [EC:]
K11315  transcriptional adapter 3
K04451  tumor protein p53
K19260  HPV major capsid protein L1
K21808  HPV minor capsid protein L2
K05631  atrophin-1 interacting protein 3 (BAI1-associated protein 1)
K01110  phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN [EC:]
K04237  partitioning defective protein 3
K06093  partitioning defective protein 6
K06069  atypical protein kinase C iota type [EC:]
K18952  atypical protein kinase C zeta type [EC:]
K04393  cell division control protein 42
K16175  protein scribble
K12076  disks large protein 1
K12075  discs large protein 2
K21098  discs large protein 3
K06094  lethal(2) giant larvae protein
K06090  crumbs 3
K06092  InaD-like protein
K06091  MAGUK p55 subfamily member 5
K03900  von Willebrand factor
K16857  thrombospondin 1
K04659  thrombospondin 2/3/4/5
K05717  fibronectin 1
K06236  collagen type I alpha
K19719  collagen type II alpha
K06237  collagen type IV alpha
K06238  collagen type VI alpha
K08131  collagen type IX alpha
K05637  laminin, alpha 1/2
K06240  laminin, alpha 3/5
K06241  laminin, alpha 4
K05636  laminin, beta 1
K06243  laminin, beta 2
K06244  laminin, beta 3
K06245  laminin, beta 4
K05635  laminin, gamma 1
K06246  laminin, gamma 2
K06247  laminin, gamma 3
K06248  chondroadherin
K06249  reelin [EC:3.4.21.-]
K06250  secreted phosphoprotein 1
K06251  vitronectin
K06252  tenascin
K06253  integrin binding sialoprotein
K06480  integrin alpha 1
K06481  integrin alpha 2
K06476  integrin alpha 2B
K06482  integrin alpha 3
K06483  integrin alpha 4
K06484  integrin alpha 5
K06485  integrin alpha 6
K06583  integrin alpha 7
K06584  integrin alpha 8
K06585  integrin alpha 9
K06586  integrin alpha 10
K06587  integrin alpha 11
K06487  integrin alpha V
K05719  integrin beta 1
K06493  integrin beta 3
K06525  integrin beta 4
K06588  integrin beta 5
K06589  integrin beta 6
K06590  integrin beta 7
K06591  integrin beta 8
K05725  focal adhesion kinase 1 [EC:]
K05760  paxillin
K03156  tumor necrosis factor superfamily, member 2
K03158  tumor necrosis factor receptor superfamily member 1A
K03171  tumor necrosis factor receptor type 1-associated DEATH domain protein
K04389  tumor necrosis factor ligand superfamily member 6
K04390  tumor necrosis factor receptor superfamily member 6
K02373  FAS-associated death domain protein
K04398  caspase 8 [EC:]
K02187  caspase 3 [EC:]
K13365  sodium/hydrogen exchange regulatory cofactor NHE-RF1
K21809  HPV protein E7
K04382  serine/threonine-protein phosphatase 2A catalytic subunit [EC:]
K03456  serine/threonine-protein phosphatase 2A regulatory subunit A
K04354  serine/threonine-protein phosphatase 2A regulatory subunit B
K11583  serine/threonine-protein phosphatase 2A regulatory subunit B''
K11584  serine/threonine-protein phosphatase 2A regulatory subunit B'
K07206  tuberous sclerosis 1
K07207  tuberous sclerosis 2
K07208  Ras homolog enriched in brain
K07203  serine/threonine-protein kinase mTOR [EC:]
K07205  eukaryotic translation initiation factor 4E binding protein 1
K04688  ribosomal protein S6 kinase beta [EC:]
K21810  HPV replication protein E1 [EC:]
K21811  HPV regulatory protein E2
K14021  Bcl-2 homologous antagonist/killer
K02158  Bcl-2-antagonist of cell death
K05089  platelet-derived growth factor receptor beta [EC:]
K00922  phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:]
K02649  phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K04456  RAC serine/threonine-protein kinase [EC:]
K07201  forkhead box protein O1
K21812  HPV protein E5
K06624  cyclin-dependent kinase inhibitor 1B
K06625  cyclin-dependent kinase inhibitor 1A
K04503  G1/S-specific cyclin-D1
K10151  G1/S-specific cyclin-D2
K10152  G1/S-specific cyclin-D3
K02089  cyclin-dependent kinase 4 [EC:]
K02091  cyclin-dependent kinase 6 [EC:]
K06626  G1/S-specific cyclin-E1
K02206  cyclin-dependent kinase 2 [EC:]
K06618  retinoblastoma-associated protein
K04681  retinoblastoma-like protein 1
K16332  retinoblastoma-like protein 2
K03062  26S proteasome regulatory subunit T2
K17454  transcription factor E2F1
K06627  cyclin-A
K04728  serine-protein kinase ATM [EC:]
K06640  serine/threonine-protein kinase ATR [EC:]
K05448  vascular endothelial growth factor A
K04467  inhibitor of nuclear factor kappa-B kinase subunit alpha [EC:]
K07209  inhibitor of nuclear factor kappa-B kinase subunit beta [EC:]
K07210  inhibitor of nuclear factor kappa-B kinase subunit gamma
K02580  nuclear factor NF-kappa-B p105 subunit
K04735  transcription factor p65
K06643  E3 ubiquitin-protein ligase Mdm2 [EC:]
K12236  transcriptional repressor NF-X1
K06067  histone deacetylase 1/2 [EC:]
K11643  chromodomain-helicase-DNA-binding protein 4 [EC:]
K09444  interferon regulatory factor 1
K03120  transcription initiation factor TFIID TATA-box-binding protein
K06751  MHC class I antigen
K14009  B-cell receptor-associated protein 31
K02145  V-type H+-transporting ATPase subunit A [EC:]
K02147  V-type H+-transporting ATPase subunit B
K02148  V-type H+-transporting ATPase subunit C
K02149  V-type H+-transporting ATPase subunit D
K02150  V-type H+-transporting ATPase subunit E
K02151  V-type H+-transporting ATPase subunit F
K02152  V-type H+-transporting ATPase subunit G
K02144  V-type H+-transporting ATPase subunit H
K02154  V-type H+-transporting ATPase subunit a
K02146  V-type H+-transporting ATPase subunit d
K02153  V-type H+-transporting ATPase subunit e
K02155  V-type H+-transporting ATPase 16kDa proteolipid subunit
K03661  V-type H+-transporting ATPase 21kDa proteolipid subunit
K03662  V-type H+-transporting ATPase S1 subunit
K04357  epidermal growth factor
K04361  epidermal growth factor receptor [EC:]
K04364  growth factor receptor-bound protein 2
K03099  son of sevenless
K02833  GTPase HRas
K07827  GTPase KRas
K07828  GTPase NRas
K04366  RAF proto-oncogene serine/threonine-protein kinase [EC:]
K04368  mitogen-activated protein kinase kinase 1 [EC:]
K04369  mitogen-activated protein kinase kinase 2 [EC:]
K04371  mitogen-activated protein kinase 1/3 [EC:]
K11987  prostaglandin-endoperoxide synthase 2 [EC:]
K04261  prostaglandin E receptor 4
K04632  guanine nucleotide-binding protein G(s) subunit alpha
K04345  protein kinase A [EC:]
K02159  apoptosis regulator BAX
K05870  cyclic AMP-responsive element-binding protein 1
K09048  cyclic AMP-responsive element-binding protein 3
K09047  cyclic AMP-responsive element-binding protein 5
K10691  E3 ubiquitin-protein ligase UBR4 [EC:]
K10389  tubulin gamma
K00873  pyruvate kinase [EC:]
K05414  interferon alpha
K05130  interferon receptor 1
K05131  interferon receptor 2
K11217  Janus kinase 1 [EC:]
K11219  non-receptor tyrosine-protein kinase TYK2 [EC:]
K11220  signal transducer and activator of transcription 1
K11221  signal transducer and activator of transcription 2
K04693  interferon regulatory factor 9
K16195  eukaryotic translation initiation factor 2-alpha kinase 2 [EC:]
K14608  2'-5'-oligoadenylate synthase-like protein
K14754  interferon-induced GTP-binding protein Mx
K12159  ubiquitin cross-reactive protein
K06052  jagged-1
K02599  Notch 1
K20994  Notch 2
K20995  Notch 3
K20996  Notch 4
K04505  presenilin 1 [EC:3.4.23.-]
K05948  fringe [EC:]
K06061  mastermind
K06053  recombining binding protein suppressor of hairless
K06054  hairy and enhancer of split 1
K09087  hairy and enhancer of split 2/6/7
K09088  hairy and enhancer of split 3
K09089  hairy and enhancer of split 4
K06055  hairy and enhancer of split 5
K09091  hairy and enhancer of split related with YRPW motif
C00575  3',5'-Cyclic AMP
C00584  Prostaglandin E2
C05981  Phosphatidylinositol-3,4,5-trisphosphate
Moody CA, Laimins LA
Human papillomavirus oncoproteins: pathways to transformation.
Nat Rev Cancer 10:550-60 (2010)
Chen J
Signaling pathways in HPV-associated cancers and therapeutic implications.
Rev Med Virol 25 Suppl 1:24-53 (2015)
Tummers B, Burg SH
High-risk human papillomavirus targets crossroads in immune signaling.
Viruses 7:2485-506 (2015)
Lehoux M, D'Abramo CM, Archambault J
Molecular mechanisms of human papillomavirus-induced carcinogenesis.
Public Health Genomics 12:268-80 (2009)
Pang CL, Thierry F
Human papillomavirus proteins as prospective therapeutic targets.
Microb Pathog 58:55-65 (2013)
Yugawa T, Kiyono T
Molecular mechanisms of cervical carcinogenesis by high-risk human papillomaviruses: novel functions of E6 and E7 oncoproteins.
Rev Med Virol 19:97-113 (2009)
Narisawa-Saito M, Kiyono T
Basic mechanisms of high-risk human papillomavirus-induced carcinogenesis: roles of E6 and E7 proteins.
Cancer Sci 98:1505-11 (2007)
Wolf JK, Ramirez PT.
The molecular biology of cervical cancer.
Cancer Invest 19:621-9 (2001)
zur Hausen H
Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis.
J Natl Cancer Inst 92:690-8 (2000)
Kim YT, Zhao M
Aberrant cell cycle regulation in cervical carcinoma.
Yonsei Med J 46:597-613 (2005)
McCance DJ
Human papillomaviruses and cell signaling.
Sci STKE 2005:pe29 (2005)
Motoyama S, Ladines-Llave CA, Luis Villanueva S, Maruo T
The role of human papilloma virus in the molecular biology of cervical carcinogenesis.
Kobe J Med Sci 50:9-19 (2004)
Tommasino M
The human papillomavirus family and its role in carcinogenesis.
Semin Cancer Biol 26:13-21 (2014)
Bello JO, Nieva LO, Paredes AC, Gonzalez AM, Zavaleta LR, Lizano M
Regulation of the Wnt/beta-Catenin Signaling Pathway by Human Papillomavirus E6 and E7 Oncoproteins.
Viruses 7:4734-55 (2015)
Shah M, Anwar MA, Park S, Jafri SS, Choi S
In silico mechanistic analysis of IRF3 inactivation and high-risk HPV E6 species-dependent drug response.
Sci Rep 5:13446 (2015)
James CD, Roberts S
Viral Interactions with PDZ Domain-Containing Proteins-An Oncogenic Trait?
Pathogens 5:E8 (2016)
Ganti K, Broniarczyk J, Manoubi W, Massimi P, Mittal S, Pim D, Szalmas A, Thatte J, Thomas M, Tomaic V, Banks L
The Human Papillomavirus E6 PDZ Binding Motif: From Life Cycle to Malignancy.
Viruses 7:3530-51 (2015)
Subbaiah VK, Kranjec C, Thomas M, Banks L
PDZ domains: the building blocks regulating tumorigenesis.
Biochem J 439:195-205 (2011)
Banks L, Pim D, Thomas M
Human tumour viruses and the deregulation of cell polarity in cancer.
Nat Rev Cancer 12:877-86 (2012)
Thomas M, Narayan N, Pim D, Tomaic V, Massimi P, Nagasaka K, Kranjec C, Gammoh N, Banks L
Human papillomaviruses, cervical cancer and cell polarity.
Oncogene 27:7018-30 (2008)
Jayshree RS, Sreenivas A, Tessy M, Krishna S
Cell intrinsic & extrinsic factors in cervical carcinogenesis.
Indian J Med Res 130:286-95 (2009)
Garnett TO, Duerksen-Hughes PJ
Modulation of apoptosis by human papillomavirus (HPV) oncoproteins.
Arch Virol 151:2321-35 (2006)
Zhang L, Wu J, Ling MT, Zhao L, Zhao KN
The role of the PI3K/Akt/mTOR signalling pathway in human cancers induced by infection with human papillomaviruses.
Mol Cancer 14:87 (2015)
Venuti A, Paolini F, Nasir L, Corteggio A, Roperto S, Campo MS, Borzacchiello G
Papillomavirus E5: the smallest oncoprotein with many functions.
Mol Cancer 10:140 (2011)
DiMaio D, Mattoon D
Mechanisms of cell transformation by papillomavirus E5 proteins.
Oncogene 20:7866-73 (2001)
Ganguly N
Human papillomavirus-16 E5 protein: oncogenic role and therapeutic value.
Cell Oncol (Dordr) 35:67-76 (2012)
DiMaio D, Petti LM
The E5 proteins.
Virology 445:99-114 (2013)
De Marco F
Oxidative stress and HPV carcinogenesis.
Viruses 5:708-31 (2013)
Wieringa HW, van der Zee AG, de Vries EG, van Vugt MA
Breaking the DNA damage response to improve cervical cancer treatment.
Cancer Treat Rev 42:30-40 (2016)
Chung CH, Gillison ML
Human papillomavirus in head and neck cancer: its role in pathogenesis and clinical implications.
Clin Cancer Res 15:6758-62 (2009)
Koromilas AE, Li S, Matlashewski G
Control of interferon signaling in human papillomavirus infection.
Cytokine Growth Factor Rev 12:157-70 (2001)
Park JS, Kim EJ, Kwon HJ, Hwang ES, Namkoong SE, Um SJ
Inactivation of interferon regulatory factor-1 tumor suppressor protein by HPV E7 oncoprotein. Implication for the E7-mediated immune evasion mechanism in cervical carcinogenesis.
J Biol Chem 275:6764-9 (2000)
Sandberg A, Lindell G, Kallstrom BN, Branca RM, Danielsson KG, Dahlberg M, Larson B, Forshed J, Lehtio J
Tumor proteomics by multivariate analysis on individual pathway data for characterization of vulvar cancer phenotypes.
Mol Cell Proteomics 11:M112.016998 (2012)
Zwerschke W, Mazurek S, Massimi P, Banks L, Eigenbrodt E, Jansen-Durr P
Modulation of type M2 pyruvate kinase activity by the human papillomavirus type 16 E7 oncoprotein.
Proc Natl Acad Sci U S A 96:1291-6 (1999)
Lu Z, Hu X, Li Y, Zheng L, Zhou Y, Jiang H, Ning T, Basang Z, Zhang C, Ke Y
Human papillomavirus 16 E6 oncoprotein interferences with insulin signaling pathway by binding to tuberin.
J Biol Chem 279:35664-70 (2004)
Xu M, Luo W, Elzi DJ, Grandori C, Galloway DA
NFX1 interacts with mSin3A/histone deacetylase to repress hTERT transcription in keratinocytes.
Mol Cell Biol 28:4819-28 (2008)
Raff AB, Woodham AW, Raff LM, Skeate JG, Yan L, Da Silva DM, Schelhaas M, Kast WM
The evolving field of human papillomavirus receptor research: a review of binding and entry.
J Virol 87:6062-72 (2013)
ko04064  NF-kappa B signaling pathway
ko04110  Cell cycle
ko04115  p53 signaling pathway
ko04150  mTOR signaling pathway
ko04151  PI3K-Akt signaling pathway
ko04210  Apoptosis
ko04310  Wnt signaling pathway
ko04330  Notch signaling pathway
ko04510  Focal adhesion
ko04520  Adherens junction
ko04530  Tight junction
ko04612  Antigen processing and presentation
ko04620  Toll-like receptor signaling pathway
ko04630  JAK-STAT signaling pathway

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