KEGG   PATHWAY: ko05163
Entry
ko05163                     Pathway                                
Name
Human cytomegalovirus infection
Description
Human cytomegalovirus (HCMV) is an enveloped, double-stranded DNA virus that is a member of beta-herpesvirus family. HCMV is best known for causing significant morbidity and mortality in immunocompromised populations. As with other herpesviruses, HCMV gB and gH/gL envelope glycoproteins are essential for virus entry. HCMV gB could activate the PDGFRA, and induce activation of the oncogenic PI3-K/AKT pathway. Though it is unlikely that HCMV by itself can act as an oncogenic factor, HCMV may have an oncomodulatory role, to catalyze an oncogenic process that has already been initiated. US28, one of the four HCMV-encoded vGPCRs (US27, US28, UL33 and UL78), also has a specific role in the oncomodulatory properties. In addition, HCMV has developed numerous mechanisms for manipulating the host immune system. The virally encoded US2, US3, US6 and US11 gene products all interfere with major histocompatibility complex (MHC) class I antigen presentation. HCMV encodes several immediate early (IE) antiapoptotic proteins (IE1, IE2, vMIA and vICA). These proteins might avoid immune clearance of infected tumor cells by cytotoxic lymphocytes and NK cells.
Class
Human Diseases; Infectious disease: viral
Pathway map
ko05163  Human cytomegalovirus infection
ko05163

Disease
H00368  Cytomegalovirus infection
Drug
D02736  Fomivirsen sodium (USAN)
D05831  Sevirumab (USAN/INN)
D07989  Fomivirsen (INN)
D09852  Regavirumab (JAN/INN)
Orthology
K22773  Betaherpesvirinae envelope glycoprotein B
K04363  platelet-derived growth factor receptor alpha [EC:2.7.10.1]
K22774  HCMV immediate-early protein 1
K22775  Cytomegalovirus viral transcription factor IE2
K00922  phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153]
K02649  phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K04456  RAC serine/threonine-protein kinase [EC:2.7.11.1]
K22776  Cytomegalovirus apoptosis inhibitor UL38
K07206  tuberous sclerosis 1
K07207  tuberous sclerosis 2
K07208  Ras homolog enriched in brain
K07203  serine/threonine-protein kinase mTOR [EC:2.7.11.1]
K07205  eukaryotic translation initiation factor 4E binding protein 1
K04688  ribosomal protein S6 kinase beta [EC:2.7.11.1]
K04467  inhibitor of nuclear factor kappa-B kinase subunit alpha [EC:2.7.11.10]
K07209  inhibitor of nuclear factor kappa-B kinase subunit beta [EC:2.7.11.10]
K07210  inhibitor of nuclear factor kappa-B kinase subunit gamma
K02580  nuclear factor NF-kappa-B p105 subunit
K04735  transcription factor p65
K04361  epidermal growth factor receptor [EC:2.7.10.1]
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:2.7.11.1]
K04368  mitogen-activated protein kinase kinase 1 [EC:2.7.12.2]
K04369  mitogen-activated protein kinase kinase 2 [EC:2.7.12.2]
K04371  mitogen-activated protein kinase 1/3 [EC:2.7.11.24]
K04375  ETS domain-containing protein Elk-1
K04684  transcription factor Sp1
K22777  Cytomegalovirus envelope glycoprotein H
K22778  Cytomegalovirus envelope glycoprotein L
K06487  integrin alpha V
K06493  integrin beta 3
K05704  tyrosine-protein kinase Src [EC:2.7.10.2]
K04392  Ras-related C3 botulinum toxin substrate 1
K07860  Ras-related C3 botulinum toxin substrate 2
K07861  Ras-related C3 botulinum toxin substrate 3
K04513  Ras homolog gene family, member A
K17834  cyclic GMP-AMP synthase [EC:2.7.7.86]
K12654  stimulator of interferon genes protein
K05410  TANK-binding kinase 1 [EC:2.7.11.10]
K22779  Cytomegalovirus tegument protein pp71
K05411  interferon regulatory factor 3
K05414  interferon alpha
K05415  interferon beta
K03156  tumor necrosis factor superfamily, member 2
K03158  tumor necrosis factor receptor superfamily member 1A
K02861  receptor-interacting serine/threonine-protein kinase 1 [EC:2.7.11.1]
K03171  tumor necrosis factor receptor type 1-associated DEATH domain protein
K09849  TNF receptor-associated factor 5
K03173  TNF receptor-associated factor 2 [EC:2.3.2.27]
K04519  interleukin 1 beta
K04386  interleukin 1 receptor type I
K22780  Cytomegalovirus tegument protein UL26
K04734  NF-kappa-B inhibitor alpha
K14624  C-C motif chemokine 2
K12499  C-C motif chemokine 5
K10030  interleukin 8
K05405  interleukin 6
K22781  HCMV envelope protein US28
K04536  guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
K04537  guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-2
K07825  guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-3
K04538  guanine nucleotide-binding protein subunit beta-4
K04539  guanine nucleotide-binding protein subunit beta-5
K07826  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
K04540  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-3
K04541  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-4
K04542  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-5
K04543  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-7
K04544  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-8
K04545  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-10
K04546  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-11
K04347  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-12
K04547  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-13
K04548  guanine nucleotide-binding protein G(T) subunit gamma-T1
K04549  guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-T2
K04634  guanine nucleotide-binding protein G(q) subunit alpha
K04635  guanine nucleotide-binding protein subunit alpha-11
K05858  phosphatidylinositol phospholipase C, beta [EC:3.1.4.11]
K04958  inositol 1,4,5-triphosphate receptor type 1
K04959  inositol 1,4,5-triphosphate receptor type 2
K04960  inositol 1,4,5-triphosphate receptor type 3
K02183  calmodulin
K04348  serine/threonine-protein phosphatase 2B catalytic subunit [EC:3.1.3.16]
K06268  serine/threonine-protein phosphatase 2B regulatory subunit
K04446  nuclear factor of activated T-cells, cytoplasmic 1
K17332  nuclear factor of activated T-cells, cytoplasmic 2
K17333  nuclear factor of activated T-cells, cytoplasmic 3
K17334  nuclear factor of activated T-cells, cytoplasmic 4
K11987  prostaglandin-endoperoxide synthase 2 [EC:1.14.99.1]
K04630  guanine nucleotide-binding protein G(i) subunit alpha
K04534  guanine nucleotide-binding protein G(o) subunit alpha
K08041  adenylate cyclase 1 [EC:4.6.1.1]
K08042  adenylate cyclase 2 [EC:4.6.1.1]
K08043  adenylate cyclase 3 [EC:4.6.1.1]
K08044  adenylate cyclase 4 [EC:4.6.1.1]
K08045  adenylate cyclase 5 [EC:4.6.1.1]
K08046  adenylate cyclase 6 [EC:4.6.1.1]
K08047  adenylate cyclase 7 [EC:4.6.1.1]
K08048  adenylate cyclase 8 [EC:4.6.1.1]
K08049  adenylate cyclase 9 [EC:4.6.1.1]
K04345  protein kinase A [EC:2.7.11.11]
K05408  C-C motif chemokine 3
K12964  C-C motif chemokine 4
K05508  C-X3-C motif chemokine 1
K04346  guanine nucleotide-binding protein subunit alpha-12
K04639  guanine nucleotide-binding protein subunit alpha-13
K12330  Rho guanine nucleotide exchange factor 1
K12331  Rho guanine nucleotide exchange factor 11
K07532  Rho guanine nucleotide exchange factor 12
K16529  A-kinase anchor protein 13
K04514  Rho-associated protein kinase 1 [EC:2.7.11.39]
K17388  Rho-associated protein kinase 2 [EC:2.7.11.39]
K02105  catenin beta 1
K04258  prostaglandin E receptor 1
K04259  prostaglandin E receptor 2
K04260  prostaglandin E receptor 3
K04261  prostaglandin E receptor 4
K04632  guanine nucleotide-binding protein G(s) subunit alpha
K03083  glycogen synthase kinase 3 beta [EC:2.7.11.26]
K04503  G1/S-specific cyclin-D1
K04377  Myc proto-oncogene protein
K05055  interleukin 6 receptor
K11217  Janus kinase 1 [EC:2.7.10.2]
K04692  signal transducer and activator of transcription 3
K05448  vascular endothelial growth factor A
K22782  Cytomegalovirus G-protein coupled receptor UL33
K04433  mitogen-activated protein kinase kinase 6 [EC:2.7.12.2]
K04441  p38 MAP kinase [EC:2.7.11.24]
K05870  cyclic AMP-responsive element-binding protein 1
K04450  cyclic AMP-dependent transcription factor ATF-2
K04374  cyclic AMP-dependent transcription factor ATF-4
K09048  cyclic AMP-responsive element-binding protein 3
K09047  cyclic AMP-responsive element-binding protein 5
K09049  cyclic AMP-dependent transcription factor ATF-6 beta
K22783  HCMV envelope glycoprotein US27
K10031  C-X-C motif chemokine 12
K04189  C-X-C chemokine receptor type 4
K02677  classical protein kinase C alpha type [EC:2.7.11.13]
K19662  classical protein kinase C beta type [EC:2.7.11.13]
K19663  classical protein kinase C gamma type [EC:2.7.11.13]
K05871  focal adhesion kinase 2 [EC:2.7.10.2]
K05725  focal adhesion kinase 1 [EC:2.7.10.2]
K05726  breast cancer anti-estrogen resistance 1
K04438  C-crk adapter molecule crk
K05760  paxillin
K21533  Herpesviridae/Poxviridae viral interleukin 10
K05134  interleukin 10 receptor alpha
K05135  interleukin 10 receptor beta
K21046  HCMV chemokine vCXCL1
K05050  C-X-C chemokine receptor type 2
K22784  HCMV glycoprotein UL22A
K04176  C-C chemokine receptor type 1
K04178  C-C chemokine receptor type 3
K04180  C-C chemokine receptor type 5
K22785  HCMV membrane glycoprotein US6
K05653  ATP-binding cassette, subfamily B (MDR/TAP), member 2 [EC:7.4.2.14]
K05654  ATP-binding cassette, subfamily B (MDR/TAP), member 3 [EC:7.4.2.14]
K08058  TAP binding protein (tapasin)
K08056  protein disulfide-isomerase A3 [EC:5.3.4.1]
K08057  calreticulin
K06751  MHC class I antigen
K08055  beta-2-microglobulin
K21050  HCMV unique short US2 glycoprotein
K22786  HCMV membrane glycoprotein US11
K22787  HCMV membrane glycoprotein US3
K21051  HCMV unique short US10 glycoprotein
K06621  cyclin-dependent kinase inhibitor 2A
K06643  E3 ubiquitin-protein ligase Mdm2 [EC:2.3.2.27]
K04451  tumor protein p53
K06625  cyclin-dependent kinase inhibitor 1A
K02089  cyclin-dependent kinase 4 [EC:2.7.11.22]
K02091  cyclin-dependent kinase 6 [EC:2.7.11.22]
K06618  retinoblastoma-associated protein
K17454  transcription factor E2F1
K09389  transcription factor E2F2
K06620  transcription factor E2F3
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:3.4.22.61]
K22788  Cytomegalovirus viral inhibitor of caspase-8-induced apoptosis
K04726  BH3 interacting domain death agonist
K02159  apoptosis regulator BAX
K14021  Bcl-2 homologous antagonist/killer
K22789  UL37 HCMV immediate early glycoprotein
K08738  cytochrome c
K04399  caspase 9 [EC:3.4.22.62]
K02187  caspase 3 [EC:3.4.22.56]
Compound
C00076  Calcium cation
C00165  Diacylglycerol
C00584  Prostaglandin E2
C01245  D-myo-Inositol 1,4,5-trisphosphate
C05981  Phosphatidylinositol-3,4,5-trisphosphate
C20640  Cyclic GMP-AMP
Reference
  Authors
Michaelis M, Doerr HW, Cinatl J
  Title
The story of human cytomegalovirus and cancer: increasing evidence and open questions.
  Journal
Neoplasia 11:1-9 (2009)
DOI:10.1593/neo.81178
Reference
  Authors
Roy S, Arav-Boger R
  Title
New cell-signaling pathways for controlling cytomegalovirus replication.
  Journal
Am J Transplant 14:1249-58 (2014)
DOI:10.1111/ajt.12725
Reference
  Authors
Cinatl J, Scholz M, Kotchetkov R, Vogel JU, Doerr HW
  Title
Molecular mechanisms of the modulatory effects of HCMV infection in tumor cell biology.
  Journal
Trends Mol Med 10:19-23 (2004)
DOI:10.1016/j.molmed.2003.11.002
Reference
  Authors
Evers DL, Wang X, Huang ES
  Title
Cellular stress and signal transduction responses to human cytomegalovirus infection.
  Journal
Microbes Infect 6:1084-93 (2004)
DOI:10.1016/j.micinf.2004.05.026
Reference
  Authors
Murray MJ, Peters NE, Reeves MB
  Title
Navigating the Host Cell Response during Entry into Sites of Latent Cytomegalovirus Infection.
  Journal
Pathogens 7:E30 (2018)
DOI:10.3390/pathogens7010030
Reference
  Authors
Campadelli-Fiume G, Collins-McMillen D, Gianni T, Yurochko AD
  Title
Integrins as Herpesvirus Receptors and Mediators of the Host Signalosome.
  Journal
Annu Rev Virol 3:215-236 (2016)
DOI:10.1146/annurev-virology-110615-035618
Reference
  Authors
Fu YZ, Su S, Gao YQ, Wang PP, Huang ZF, Hu MM, Luo WW, Li S, Luo MH, Wang YY, Shu HB
  Title
Human Cytomegalovirus Tegument Protein UL82 Inhibits STING-Mediated Signaling to Evade Antiviral Immunity.
  Journal
Cell Host Microbe 21:231-243 (2017)
DOI:10.1016/j.chom.2017.01.001
Reference
  Authors
Hancock MH, Nelson JA
  Title
Modulation of the NFkappab Signalling Pathway by Human Cytomegalovirus.
  Journal
Virology (Hyderabad) 1:104 (2017)
Reference
  Authors
Rahman MM, McFadden G
  Title
Modulation of NF-kappaB signalling by microbial pathogens.
  Journal
Nat Rev Microbiol 9:291-306 (2011)
DOI:10.1038/nrmicro2539
Reference
  Authors
Zhang J, Feng H, Xu S, Feng P
  Title
Hijacking GPCRs by viral pathogens and tumor.
  Journal
Biochem Pharmacol 114:69-81 (2016)
DOI:10.1016/j.bcp.2016.03.021
Reference
  Authors
Lee S, Chung YH, Lee C
  Title
US28, a Virally-Encoded GPCR as an Antiviral Target for Human Cytomegalovirus Infection.
  Journal
Biomol Ther (Seoul) 25:69-79 (2017)
DOI:10.4062/biomolther.2016.208
Reference
  Authors
Langemeijer EV, Slinger E, de Munnik S, Schreiber A, Maussang D, Vischer H, Verkaar F, Leurs R, Siderius M, Smit MJ
  Title
Constitutive beta-catenin signaling by the viral chemokine receptor US28.
  Journal
PLoS One 7:e48935 (2012)
DOI:10.1371/journal.pone.0048935
Reference
  Authors
Couty JP, Gershengorn MC
  Title
G-protein-coupled receptors encoded by human herpesviruses.
  Journal
Trends Pharmacol Sci 26:405-11 (2005)
DOI:10.1016/j.tips.2005.06.004
Reference
  Authors
Fiallos E, Judkins J, Matlaf L, Prichard M, Dittmer D, Cobbs C, Soroceanu L
  Title
Human cytomegalovirus gene expression in long-term infected glioma stem cells.
  Journal
PLoS One 9:e116178 (2014)
DOI:10.1371/journal.pone.0116178
Reference
  Authors
Vischer HF, Siderius M, Leurs R, Smit MJ
  Title
Herpesvirus-encoded GPCRs: neglected players in inflammatory and proliferative diseases?
  Journal
Nat Rev Drug Discov 13:123-39 (2014)
DOI:10.1038/nrd4189
Reference
  Authors
Slinger E, Langemeijer E, Siderius M, Vischer HF, Smit MJ
  Title
Herpesvirus-encoded GPCRs rewire cellular signaling.
  Journal
Mol Cell Endocrinol 331:179-84 (2011)
DOI:10.1016/j.mce.2010.04.007
Reference
  Authors
Murphy PM
  Title
Viral exploitation and subversion of the immune system through chemokine mimicry.
  Journal
Nat Immunol 2:116-22 (2001)
DOI:10.1038/84214
Reference
  Authors
Vischer HF, Leurs R, Smit MJ
  Title
HCMV-encoded G-protein-coupled receptors as constitutively active modulators of cellular signaling networks.
  Journal
Trends Pharmacol Sci 27:56-63 (2006)
DOI:10.1016/j.tips.2005.11.006
Reference
  Authors
de Munnik SM, Smit MJ, Leurs R, Vischer HF
  Title
Modulation of cellular signaling by herpesvirus-encoded G protein-coupled receptors.
  Journal
Front Pharmacol 6:40 (2015)
DOI:10.3389/fphar.2015.00040
Reference
  Authors
Michelson S
  Title
Consequences of human cytomegalovirus mimicry.
  Journal
Hum Immunol 65:465-75 (2004)
DOI:10.1016/j.humimm.2004.02.002
Reference
  Authors
Tu CC, Arnolds KL, O'Connor CM, Spencer JV
  Title
Human Cytomegalovirus UL111A and US27 Gene Products Enhance the CXCL12/CXCR4 Signaling Axis via Distinct Mechanisms.
  Journal
J Virol 92:e01981-17 (2018)
DOI:10.1128/JVI.01981-17
Reference
  Authors
Busillo JM, Benovic JL
  Title
Regulation of CXCR4 signaling.
  Journal
Biochim Biophys Acta 1768:952-63 (2007)
DOI:10.1016/j.bbamem.2006.11.002
Reference
  Authors
Noriega V, Redmann V, Gardner T, Tortorella D
  Title
Diverse immune evasion strategies by human cytomegalovirus.
  Journal
Immunol Res 54:140-51 (2012)
DOI:10.1007/s12026-012-8304-8
Reference
  Authors
Loureiro J, Ploegh HL
  Title
Antigen presentation and the ubiquitin-proteasome system in host-pathogen interactions.
  Journal
Adv Immunol 92:225-305 (2006)
DOI:10.1016/S0065-2776(06)92006-9
Reference
  Authors
Fortunato EA, McElroy AK, Sanchez I, Spector DH
  Title
Exploitation of cellular signaling and regulatory pathways by human cytomegalovirus.
  Journal
Trends Microbiol 8:111-9 (2000)
DOI:10.1016/S0966-842X(00)01699-1
Reference
  Authors
Cinatl J Jr, Scholz M, Doerr HW
  Title
Role of tumor cell immune escape mechanisms in cytomegalovirus-mediated oncomodulation.
  Journal
Med Res Rev 25:167-85 (2005)
DOI:10.1002/med.20018
Reference
  Authors
Cinatl J Jr, Vogel JU, Kotchetkov R, Wilhelm Doerr H
  Title
Oncomodulatory signals by regulatory proteins encoded by human cytomegalovirus: a novel role for viral infection in tumor progression.
  Journal
FEMS Microbiol Rev 28:59-77 (2004)
DOI:10.1016/j.femsre.2003.07.005
Reference
  Authors
Castillo JP, Kowalik TF
  Title
Human cytomegalovirus immediate early proteins and cell growth control.
  Journal
Gene 290:19-34 (2002)
DOI:10.1016/S0378-1119(02)00566-8
Reference
  Authors
Kalejta RF
  Title
Human cytomegalovirus pp71: a new viral tool to probe the mechanisms of cell cycle progression and oncogenesis controlled by the retinoblastoma family of tumor suppressors.
  Journal
J Cell Biochem 93:37-45 (2004)
DOI:10.1002/jcb.20177
Reference
  Authors
Brune W
  Title
Inhibition of programmed cell death by cytomegaloviruses.
  Journal
Virus Res 157:144-50 (2011)
DOI:10.1016/j.virusres.2010.10.012
Reference
  Authors
Brune W, Andoniou CE
  Title
Die Another Day: Inhibition of Cell Death Pathways by Cytomegalovirus.
  Journal
Viruses 9:E249 (2017)
DOI:10.3390/v9090249
Reference
  Authors
Yamin R, Lecker LSM, Weisblum Y, Vitenshtein A, Le-Trilling VTK, Wolf DG, Mandelboim O
  Title
HCMV vCXCL1 Binds Several Chemokine Receptors and Preferentially Attracts Neutrophils over NK Cells by Interacting with CXCR2.
  Journal
Cell Rep 15:1542-1553 (2016)
DOI:10.1016/j.celrep.2016.04.042
Reference
  Authors
Wang X, Sanchez J, Stone MJ, Payne RJ
  Title
Sulfation of the Human Cytomegalovirus Protein UL22A Enhances Binding to the Chemokine RANTES.
  Journal
Angew Chem Int Ed Engl 56:8490-8494 (2017)
DOI:10.1002/anie.201703059
Related
pathway
ko00590  Arachidonic acid metabolism
ko03050  Proteasome
ko04010  MAPK signaling pathway
ko04064  NF-kappa B signaling pathway
ko04110  Cell cycle
ko04150  mTOR signaling pathway
ko04151  PI3K-Akt signaling pathway
ko04210  Apoptosis
ko04612  Antigen processing and presentation
ko04623  Cytosolic DNA-sensing pathway
ko04630  JAK-STAT signaling pathway
ko04668  TNF signaling pathway
ko04810  Regulation of actin cytoskeleton
LinkDB

DBGET integrated database retrieval system