KEGG   PATHWAY: oga05212
Entry
oga05212                    Pathway                                
Name
Pancreatic cancer - Otolemur garnettii (small-eared galago)
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
oga05212  Pancreatic cancer
oga05212

Disease
H00019  Pancreatic cancer
Organism
Otolemur garnettii (small-eared galago) [GN:oga]
Gene
100940650  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X5 [KO:K04688] [EC:2.7.11.1]
100941062  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
100941755  BAK1; bcl-2 homologous antagonist/killer isoform X1 [KO:K14021]
100942819  E2F3; transcription factor E2F3 [KO:K06620]
100943080  [KO:K06621]
100944758  RALA; ras-related protein Ral-A [KO:K07834]
100945636  RALBP1; ralA-binding protein 1 [KO:K08773]
100945805  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
100945977  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100946157  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
100946725  CDKN1A; cyclin-dependent kinase inhibitor 1 [KO:K06625]
100946928  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
100947138  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
100947706  [KO:K04393]
100947929  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
100948274  RAC3; ras-related C3 botulinum toxin substrate 3 [KO:K07861]
100949554  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X1 [KO:K04467] [EC:2.7.11.10]
100949640  TGFB1; transforming growth factor beta-1 isoform X2 [KO:K13375]
100949858  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
100950302  EGFR; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
100950310  RALB; ras-related protein Ral-B [KO:K07835]
100950782  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
100950842  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma isoform X2 [KO:K04402]
100950992  CDC42; cell division control protein 42 homolog [KO:K04393]
100951061  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
100951369  RAC1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]
100951476  RB1; retinoblastoma-associated protein [KO:K06618]
100951533  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
100952236  CDK6; cyclin-dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
100952580  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X2 [KO:K02649]
100952650  BRCA2; breast cancer type 2 susceptibility protein [KO:K08775]
100953032  BCL2L1; bcl-2-like protein 1 [KO:K04570]
100953050  KRAS; GTPase KRas isoform X3 [KO:K07827]
100953115  TGFBR1; TGF-beta receptor type-1 isoform X1 [KO:K04674] [EC:2.7.11.30]
100953367  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
100953476  RALGDS; ral guanine nucleotide dissociation stimulator isoform X1 [KO:K08732]
100953964  ERBB2; receptor tyrosine-protein kinase erbB-2 [KO:K05083] [EC:2.7.10.1]
100954109  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
100955095  JAK1; tyrosine-protein kinase JAK1 [KO:K11217] [EC:2.7.10.2]
100955213  TGFB3; transforming growth factor beta-3 [KO:K13377]
100955276  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100955336  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
100955502  SMAD4; mothers against decapentaplegic homolog 4 [KO:K04501]
100956747  TGFB2; transforming growth factor beta-2 isoform X2 [KO:K13376]
100956762  STAT1; signal transducer and activator of transcription 1-alpha/beta [KO:K11220]
100956838  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649]
100956861  E2F2; transcription factor E2F2 [KO:K09389]
100957114  E2F1; transcription factor E2F1 [KO:K17454]
100957169  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
100957182  RAC2; ras-related C3 botulinum toxin substrate 2 [KO:K07860]
100957225  PLD2; phospholipase D2 [KO:K01115] [EC:3.1.4.4]
100957285  BAX; apoptosis regulator BAX [KO:K02159]
100957343  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
100957753  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
100957904  CASP9; caspase-9 isoform X1 [KO:K04399] [EC:3.4.22.62]
100957990  RELA; transcription factor p65 isoform X3 [KO:K04735]
100958469  STAT3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
100958883  IKBKG; NF-kappa-B essential modulator isoform X1 [KO:K07210]
100958947  CCND1; G1/S-specific cyclin-D1 [KO:K04503]
100959235  TGFA; protransforming growth factor alpha isoform X2 [KO:K08774]
100959450  PLD1; phospholipase D1 isoform X4 [KO:K01115] [EC:3.1.4.4]
100959686  EGF; pro-epidermal growth factor [KO:K04357]
100959825  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
100959926  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
100960272  VEGFA; vascular endothelial growth factor A [KO:K05448]
100960275  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
100960336  SMAD2; mothers against decapentaplegic homolog 2 [KO:K04500]
100960589  CDK4; cyclin-dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
100960821  TGFBR2; TGF-beta receptor type-2 isoform X2 [KO:K04388] [EC:2.7.11.30]
100962223  SMAD3; mothers against decapentaplegic homolog 3 [KO:K23605]
100962269  RAD51; DNA repair protein RAD51 homolog 1 [KO:K04482]
100962306  BAD; bcl2-associated agonist of cell death [KO:K02158]
100962402  DDB2; DNA damage-binding protein 2 [KO:K10140]
100963622  TP53; cellular tumor antigen p53 [KO:K04451]
100964965  ARHGEF6; rho guanine nucleotide exchange factor 6 isoform X1 [KO:K05729]
100966233  POLK; DNA polymerase kappa isoform X1 [KO:K03511] [EC:2.7.7.7]
100967053  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
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
oga04010  MAPK signaling pathway
oga04012  ErbB signaling pathway
oga04110  Cell cycle
oga04115  p53 signaling pathway
oga04151  PI3K-Akt signaling pathway
oga04210  Apoptosis
oga04350  TGF-beta signaling pathway
oga04370  VEGF signaling pathway
oga04630  JAK-STAT signaling pathway
KO pathway
ko05212   

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