KEGG   PATHWAY: hai05212
Entry
hai05212                    Pathway                                
Name
Pancreatic cancer - Hipposideros armiger (great roundleaf bat)
Description
Infiltrating ductal adenocarcinoma is the most common malignancy of the pancreas. When most investigators use the term 'pancreatic cancer' they are referring to pancreatic ductal adenocarcinoma (PDA). Normal duct epithelium progresses to infiltrating cancer through a series of histologically defined precursors (PanINs). The overexpression of HER-2/neu and activating point mutations in the K-ras gene occur early, inactivation of the p16 gene at an intermediate stage, and the inactivation of p53, SMAD4, and BRCA2 occur relatively late. Activated K-ras engages multiple effector pathways. Although EGF receptors are conventionally regarded as upstream activators of RAS proteins, they can also act as RAS signal transducers via RAS-induced autocrine activation of the EGFR family ligands. Moreover, PDA shows extensive genomic instability and aneuploidy. Telomere attrition and mutations in p53 and BRCA2 are likely to contribute to these phenotypes. Inactivation of the SMAD4 tumour suppressor gene leads to loss of the inhibitory influence of the transforming growth factor-beta signalling pathway.
Class
Human Diseases; Cancer: specific types
Pathway map
hai05212  Pancreatic cancer
hai05212

Disease
H00019  Pancreatic cancer
Organism
Hipposideros armiger (great roundleaf bat) [GN:hai]
Gene
109371666  PLD1; phospholipase D1 [KO:K01115] [EC:3.1.4.4]
109372541  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
109372681  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
109373362  [KO:K04570]
109373579  SMAD4; mothers against decapentaplegic homolog 4 [KO:K04501]
109373596  CDK6; cyclin-dependent kinase 6 isoform X1 [KO:K02091] [EC:2.7.11.22]
109373811  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
109374090  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
109374675  [KO:K06621]
109374859  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
109376563  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
109376590  TGFB1; transforming growth factor beta-1 [KO:K13375]
109377242  E2F1; transcription factor E2F1 [KO:K17454]
109377344  IKBKG; NF-kappa-B essential modulator isoform X1 [KO:K07210]
109377948  [KO:K04440] [EC:2.7.11.24]
109379436  EGF; pro-epidermal growth factor [KO:K04357]
109379632  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X1 [KO:K04467] [EC:2.7.11.10]
109379764  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
109380150  RAC1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]
109380800  ERBB2; receptor tyrosine-protein kinase erbB-2 isoform X1 [KO:K05083] [EC:2.7.10.1]
109381083  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
109381205  TGFB2; transforming growth factor beta-2 isoform X1 [KO:K13376]
109381238  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
109381262  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
109381302  CASP9; caspase-9 isoform X1 [KO:K04399] [EC:3.4.22.62]
109381619  TGFB3; transforming growth factor beta-3 isoform X1 [KO:K13377]
109381623  E2F3; transcription factor E2F3 isoform X1 [KO:K06620]
109381899  POLK; DNA polymerase kappa [KO:K03511] [EC:2.7.7.7]
109382359  RALGDS; ral guanine nucleotide dissociation stimulator [KO:K08732]
109382484  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
109382864  VEGFA; vascular endothelial growth factor A [KO:K05448]
109384082  RAD51; DNA repair protein RAD51 homolog 1 isoform X1 [KO:K04482]
109384219  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
109384256  BAD; bcl2-associated agonist of cell death [KO:K02158]
109384322  RELA; transcription factor p65 isoform X1 [KO:K04735]
109384429  BCL2L1; bcl-2-like protein 1 isoform X1 [KO:K04570]
109384548  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
109384926  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
109384938  JAK1; tyrosine-protein kinase JAK1 [KO:K11217] [EC:2.7.10.2]
109385242  SMAD3; mothers against decapentaplegic homolog 3 [KO:K23605]
109385252  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
109385353  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
109385384  TGFA; protransforming growth factor alpha isoform X1 [KO:K08774]
109385803  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
109385878  [KO:K04456] [EC:2.7.11.1]
109386279  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
109386421  TGFBR1; TGF-beta receptor type-1 [KO:K04674] [EC:2.7.11.30]
109386609  RALBP1; ralA-binding protein 1 [KO:K08773]
109386699  E2F2; transcription factor E2F2 isoform X1 [KO:K09389]
109387138  RB1; retinoblastoma-associated protein [KO:K06618]
109388018  BRCA2; breast cancer type 2 susceptibility protein isoform X1 [KO:K08775]
109388212  SMAD2; mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
109388365  EGFR; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
109388814  RALA; ras-related protein Ral-A [KO:K07834]
109389264  KRAS; GTPase KRas isoform X1 [KO:K07827]
109389297  CCND1; G1/S-specific cyclin-D1 isoform X1 [KO:K04503]
109390202  DDB2; DNA damage-binding protein 2 [KO:K10140]
109390584  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
109390747  CDK4; cyclin-dependent kinase 4 isoform X1 [KO:K02089] [EC:2.7.11.22]
109391068  BAX; apoptosis regulator BAX [KO:K02159]
109392215  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
109392454  BAK1; bcl-2 homologous antagonist/killer isoform X1 [KO:K14021]
109392748  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
109393041  RAC3; ras-related C3 botulinum toxin substrate 3 isoform X1 [KO:K07861]
109393276  STAT1; signal transducer and activator of transcription 1-alpha/beta [KO:K11220]
109394108  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
109394441  TGFBR2; TGF-beta receptor type-2 [KO:K04388] [EC:2.7.11.30]
109394502  RAC2; ras-related C3 botulinum toxin substrate 2 [KO:K07860]
109394672  TP53; cellular tumor antigen p53 isoform X1 [KO:K04451]
109394696  PLD2; phospholipase D2 isoform X1 [KO:K01115] [EC:3.1.4.4]
109394900  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
109395605  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
109395763  STAT3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
109395865  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
109395991  CDKN1A; cyclin-dependent kinase inhibitor 1 [KO:K06625]
109396173  ARHGEF6; rho guanine nucleotide exchange factor 6 isoform X1 [KO:K05729]
109396687  RALB; ras-related protein Ral-B [KO:K07835]
109396744  CDC42; cell division control protein 42 homolog isoform X1 [KO:K04393]
Compound
C00416  Phosphatidate
C05981  Phosphatidylinositol-3,4,5-trisphosphate
Reference
  Authors
Von Hoff D, Evans D, Hruban R (ed).
  Title
Pancreatic cancer
  Journal
Jones and Bartlett publishers (2005)
Reference
  Authors
Niitsu Y, Yokota J (ed).
  Title
[Oncogenes and Tumor Suppressor Genes for Medical Oncologist] (In Japanese)
  Journal
Nankodo (1999)
Reference
  Authors
Bardeesy N, DePinho RA.
  Title
Pancreatic cancer biology and genetics.
  Journal
Nat Rev Cancer 2:897-909 (2002)
DOI:10.1038/nrc949
Reference
  Authors
Bardeesy N, Sharpless NE, DePinho RA, Merlino G.
  Title
The genetics of pancreatic adenocarcinoma: a roadmap for a mouse model.
  Journal
Semin Cancer Biol 11:201-18 (2001)
DOI:10.1006/scbi.2000.0371
Reference
  Authors
Cowgill SM, Muscarella P.
  Title
The genetics of pancreatic cancer.
  Journal
Am J Surg 186:279-86 (2003)
DOI:10.1016/S0002-9610(03)00226-5
Reference
  Authors
Hezel AF, Kimmelman AC, Stanger BZ, Bardeesy N, Depinho RA.
  Title
Genetics and biology of pancreatic ductal adenocarcinoma.
  Journal
Genes Dev 20:1218-49 (2006)
DOI:10.1101/gad.1415606
Reference
  Authors
Shields JM, Pruitt K, McFall A, Shaub A, Der CJ.
  Title
Understanding Ras: 'it ain't over 'til it's over'.
  Journal
Trends Cell Biol 10:147-54 (2000)
DOI:10.1016/S0962-8924(00)01740-2
Reference
  Authors
Holbro T, Civenni G, Hynes NE.
  Title
The ErbB receptors and their role in cancer progression.
  Journal
Exp Cell Res 284:99-110 (2003)
DOI:10.1016/S0014-4827(02)00099-X
Reference
  Authors
Marmor MD, Skaria KB, Yarden Y.
  Title
Signal transduction and oncogenesis by ErbB/HER receptors.
  Journal
Int J Radiat Oncol Biol Phys 58:903-13 (2004)
DOI:10.1016/j.ijrobp.2003.06.002
Reference
  Authors
DeArmond D, Brattain MG, Jessup JM, Kreisberg J, Malik S, Zhao S, Freeman JW.
  Title
Autocrine-mediated ErbB-2 kinase activation of STAT3 is required for growth factor independence of pancreatic cancer cell lines.
  Journal
Oncogene 22:7781-95 (2003)
DOI:10.1038/sj.onc.1206966
Reference
  Authors
Wei D, Le X, Zheng L, Wang L, Frey JA, Gao AC, Peng Z, Huang S, Xiong HQ, Abbruzzese JL, Xie K.
  Title
Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis.
  Journal
Oncogene 22:319-29 (2003)
DOI:10.1038/sj.onc.1206122
Reference
  Authors
Toyonaga T, Nakano K, Nagano M, Zhao G, Yamaguchi K, Kuroki S, Eguchi T, Chijiiwa K, Tsuneyoshi M, Tanaka M.
  Title
Blockade of constitutively activated Janus kinase/signal transducer and activator of transcription-3 pathway inhibits growth of human pancreatic cancer.
  Journal
Cancer Lett 201:107-16 (2003)
DOI:10.1016/S0304-3835(03)00482-8
Reference
  Authors
Schmid RM.
  Title
Genetic basis of pancreatic cancer.
  Journal
Best Pract Res Clin Gastroenterol 16:421-33 (2002)
DOI:10.1053/bega.2002.0316
Reference
  Authors
Elliott RL, Blobe GC.
  Title
Role of transforming growth factor Beta in human cancer.
  Journal
J Clin Oncol 23:2078-93 (2005)
DOI:10.1200/JCO.2005.02.047
Reference
  Authors
Rudkin TM, Foulkes WD.
  Title
BRCA2: breaks, mistakes and failed separations.
  Journal
Trends Mol Med 11:145-8 (2005)
DOI:10.1016/j.molmed.2005.02.003
Reference
  Authors
Venkitaraman AR.
  Title
Functions of BRCA1 and BRCA2 in the biological response to DNA damage.
  Journal
J Cell Sci 114:3591-8 (2001)
Reference
  Authors
Chang Z, Li Z, Wang X, Kang Y, Yuan Y, Niu J, Wang H, Chatterjee D, Fleming JB, Li M, Abbruzzese JL, Chiao PJ
  Title
Deciphering the mechanisms of tumorigenesis in human pancreatic ductal epithelial cells.
  Journal
Clin Cancer Res 19:549-59 (2013)
DOI:10.1158/1078-0432.CCR-12-0032
Related
pathway
hai04010  MAPK signaling pathway
hai04012  ErbB signaling pathway
hai04110  Cell cycle
hai04115  p53 signaling pathway
hai04151  PI3K-Akt signaling pathway
hai04210  Apoptosis
hai04350  TGF-beta signaling pathway
hai04370  VEGF signaling pathway
hai04630  JAK-STAT signaling pathway
KO pathway
ko05212   

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