KEGG   PATHWAY: dle05212
Entry
dle05212                    Pathway                                

Name
Pancreatic cancer - Delphinapterus leucas (beluga whale)
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
dle05212  Pancreatic cancer
dle05212

Organism
Delphinapterus leucas (beluga whale) [GN:dle]
Gene
111176851  KRAS; GTPase KRas [KO:K07827]
111173839  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
111179235  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
111187262  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
111166652  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
111185984  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
111175760  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
111164588  ARHGEF6; rho guanine nucleotide exchange factor 6 isoform X1 [KO:K05729]
111181886  RAC1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]
111186216  RAC2; ras-related C3 botulinum toxin substrate 2 isoform X1 [KO:K07860]
111182681  RAC3; ras-related C3 botulinum toxin substrate 3 isoform X2 [KO:K07861]
111179110  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
111183745  RELA; transcription factor p65 isoform X1 [KO:K04735]
111177559  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
111176008  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
111180855  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
111172396  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X1 [KO:K04467] [EC:2.7.11.10]
111173552  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
111170969  IKBKG; NF-kappa-B essential modulator isoform X1 [KO:K07210]
111183810  BAD; bcl2-associated agonist of cell death [KO:K02158]
111184326  BCL2L1; bcl-2-like protein 1 isoform X1 [KO:K04570]
111187099  CASP9; caspase-9 [KO:K04399] [EC:3.4.22.62]
111165554  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
111177653  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
111168973  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
111177745  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
111163022  MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
111182181  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
111168108  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
111169265  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
111169895  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
111177083  RALGDS; ral guanine nucleotide dissociation stimulator isoform X1 [KO:K08732]
111184488  RALA; ras-related protein Ral-A [KO:K07834]
111170386  RALB; ras-related protein Ral-B [KO:K07835]
111163028  RALBP1; ralA-binding protein 1 [KO:K08773]
111163214  CDC42; cell division control protein 42 homolog isoform X1 [KO:K04393]
111175094  LOW QUALITY PROTEIN: cell division control protein 42 homolog [KO:K04393]
111185941  PLD2; phospholipase D2 isoform X1 [KO:K01115] [EC:3.1.4.4]
111174011  PLD1; phospholipase D1 isoform X3 [KO:K01115] [EC:3.1.4.4]
111167945  TGFA; protransforming growth factor alpha isoform X1 [KO:K08774]
111186135  EGF; pro-epidermal growth factor [KO:K04357]
111184548  EGFR; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
111166300  ERBB2; receptor tyrosine-protein kinase erbB-2 [KO:K05083] [EC:2.7.10.1]
111187265  MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
111183673  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
111163760  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
111178461  JAK1; tyrosine-protein kinase JAK1 [KO:K11217] [EC:2.7.10.2]
111166491  STAT3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
111171663  STAT1; signal transducer and activator of transcription 1-alpha/beta isoform X1 [KO:K11220]
111178866  VEGFA; vascular endothelial growth factor A isoform X1 [KO:K05448]
111163175  cyclin-dependent kinase inhibitor 2A-like isoform X1 [KO:K06621]
111173824  CDK4; cyclin-dependent kinase 4 isoform X1 [KO:K02089] [EC:2.7.11.22]
111180943  CDK6; cyclin-dependent kinase 6 isoform X1 [KO:K02091] [EC:2.7.11.22]
111183632  CCND1; G1/S-specific cyclin-D1 [KO:K04503]
111175081  RB1; retinoblastoma-associated protein [KO:K06618]
111184273  E2F1; transcription factor E2F1 isoform X1 [KO:K17454]
111163373  E2F2; transcription factor E2F2 isoform X1 [KO:K09389]
111181407  E2F3; transcription factor E2F3 isoform X2 [KO:K06620]
111185755  TP53; cellular tumor antigen p53 [KO:K04451]
111178743  CDKN1A; cyclin-dependent kinase inhibitor 1 [KO:K06625]
111170922  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
111178438  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
111167640  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
111180640  BAX; apoptosis regulator BAX isoform X1 [KO:K02159]
111178690  BAK1; bcl-2 homologous antagonist/killer isoform X1 [KO:K14021]
111183968  DDB2; DNA damage-binding protein 2 isoform X1 [KO:K10140]
111185272  POLK; DNA polymerase kappa [KO:K03511] [EC:2.7.7.7]
111180824  TGFB1; transforming growth factor beta-1 proprotein isoform X1 [KO:K13375]
111177477  TGFB2; transforming growth factor beta-2 proprotein isoform X1 [KO:K13376]
111176232  TGFB3; transforming growth factor beta-3 proprotein [KO:K13377]
111188083  TGFBR1; TGF-beta receptor type-1 isoform X1 [KO:K04674] [EC:2.7.11.30]
111164342  TGFBR2; TGF-beta receptor type-2 [KO:K04388] [EC:2.7.11.30]
111180276  SMAD2; mothers against decapentaplegic homolog 2 [KO:K04500]
111177751  SMAD3; mothers against decapentaplegic homolog 3 isoform X1 [KO:K23605]
111180252  SMAD4; mothers against decapentaplegic homolog 4 [KO:K04501]
111175212  BRCA2; breast cancer type 2 susceptibility protein [KO:K08775]
111181740  RAD51; DNA repair protein RAD51 homolog 1 [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
dle04010  MAPK signaling pathway
dle04012  ErbB signaling pathway
dle04110  Cell cycle
dle04115  p53 signaling pathway
dle04151  PI3K-Akt signaling pathway
dle04210  Apoptosis
dle04350  TGF-beta signaling pathway
dle04370  VEGF signaling pathway
dle04630  JAK-STAT signaling pathway
KO pathway
ko05212   
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