KEGG   PATHWAY: bom05212
Entry
bom05212                    Pathway                                

Name
Pancreatic cancer - Bos mutus (wild yak)
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
bom05212  Pancreatic cancer
bom05212

Organism
Bos mutus (wild yak) [GN:bom]
Gene
102286500  KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
102274553  PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
102274461  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
102277548  PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
102266922  PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
102280296  PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
102286868  PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
102269505  ARHGEF6; Rac/Cdc42 guanine nucleotide exchange factor 6 [KO:K05729]
102273253  RAC1; ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) [KO:K04392]
102277352  RAC2; ras-related C3 botulinum toxin substrate 2 (rho family, small GTP binding protein Rac2) [KO:K07860]
102286986  RAC3; ras-related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3) [KO:K07861]
102286969  NFKB1; nuclear factor kappa B subunit 1 [KO:K02580]
102268417  RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735]
102275199  AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]
102265427  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
102283212  AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]
102281886  CHUK; conserved helix-loop-helix ubiquitous kinase [KO:K04467] [EC:2.7.11.10]
102281443  IKBKB; inhibitor of nuclear factor kappa B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
102287968  IKBKG; inhibitor of nuclear factor kappa B kinase subunit gamma [KO:K07210]
102275975  BAD; BCL2 associated agonist of cell death [KO:K02158]
102277355  BCL2L1; BCL2 like 1 [KO:K04570]
102271380  bcl-2-like protein 1 [KO:K04570]
102268660  CASP9; caspase 9 [KO:K04399] [EC:3.4.22.62]
102285079  ARAF; A-Raf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:2.7.11.1]
102278631  BRAF; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:2.7.11.1]
102288216  RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
102280670  MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
102272368  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
102284931  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
102277976  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
102266960  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
102272421  MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
102284256  RALGDS; ral guanine nucleotide dissociation stimulator [KO:K08732]
102278480  RALA; RAS like proto-oncogene A [KO:K07834]
102284066  RALB; RAS like proto-oncogene B [KO:K07835]
102276164  RALBP1; ralA binding protein 1 [KO:K08773]
102266310  CDC42; cell division cycle 42 [KO:K04393]
102279771  PLD1; phospholipase D1 [KO:K01115] [EC:3.1.4.4]
102288325  PLD2; phospholipase D2 [KO:K01115] [EC:3.1.4.4]
102264981  TGFA; transforming growth factor alpha [KO:K08774]
102285914  EGF; epidermal growth factor [KO:K04357]
102269868  epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
102267975  ERBB2; erb-b2 receptor tyrosine kinase 2 [KO:K05083] [EC:2.7.10.1]
102281727  MTOR; mechanistic target of rapamycin [KO:K07203] [EC:2.7.11.1]
102285710  RPS6KB1; ribosomal protein S6 kinase B1 [KO:K04688] [EC:2.7.11.1]
102271079  RPS6KB2; ribosomal protein S6 kinase B2 [KO:K04688] [EC:2.7.11.1]
102286137  JAK1; Janus kinase 1 [KO:K11217] [EC:2.7.10.2]
102282282  STAT3; signal transducer and activator of transcription 3 [KO:K04692]
102283508  STAT1; signal transducer and activator of transcription 1 [KO:K11220]
102270607  VEGFA; vascular endothelial growth factor A [KO:K05448]
102284461  CDKN2A; cyclin dependent kinase inhibitor 2A [KO:K06621]
102278545  CDK4; cyclin dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
102264992  CDK6; cyclin dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
102270546  CCND1; cyclin D1 [KO:K04503]
102267169  RB1; RB transcriptional corepressor 1 [KO:K06618]
102274863  E2F1; E2F transcription factor 1 [KO:K17454]
102268181  E2F2; E2F transcription factor 2 [KO:K09389]
102270876  E2F3; E2F transcription factor 3 [KO:K06620]
102272370  TP53; tumor protein p53 [KO:K04451]
102268672  CDKN1A; cyclin dependent kinase inhibitor 1A [KO:K06625]
102276116  GADD45G; growth arrest and DNA damage inducible gamma [KO:K04402]
102266978  GADD45B; growth arrest and DNA damage inducible beta [KO:K04402]
102288000  GADD45A; growth arrest and DNA damage inducible alpha [KO:K04402]
102279740  BAX; BCL2 associated X, apoptosis regulator [KO:K02159]
102266544  BAK1; BCL2 antagonist/killer 1 [KO:K14021]
102272760  DDB2; damage specific DNA binding protein 2 [KO:K10140]
102269608  POLK; DNA polymerase kappa [KO:K03511] [EC:2.7.7.7]
102283357  TGFB1; transforming growth factor beta 1 [KO:K13375]
102283491  TGFB2; transforming growth factor beta 2 [KO:K13376]
102265567  TGFB3; transforming growth factor beta 3 [KO:K13377]
102283685  TGFBR1; transforming growth factor beta receptor 1 [KO:K04674] [EC:2.7.11.30]
102267018  TGFBR2; transforming growth factor beta receptor 2 [KO:K04388] [EC:2.7.11.30]
102286495  SMAD2; mothers against decapentaplegic homolog 2 [KO:K04500]
102282627  SMAD3; SMAD family member 3 [KO:K23605]
102265995  SMAD4; SMAD family member 4 [KO:K04501]
102276437  BRCA2; BRCA2, DNA repair associated [KO:K08775]
102277254  RAD51; RAD51 recombinase [KO:K04482]
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
(Japanese)
  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
bom04010  MAPK signaling pathway
bom04012  ErbB signaling pathway
bom04110  Cell cycle
bom04115  p53 signaling pathway
bom04151  PI3K-Akt signaling pathway
bom04210  Apoptosis
bom04350  TGF-beta signaling pathway
bom04370  VEGF signaling pathway
bom04630  JAK-STAT signaling pathway
KO pathway
ko05212   
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