KEGG   PATHWAY: ray05212
Entry
ray05212                    Pathway                                

Name
Pancreatic cancer - Rousettus aegyptiacus (Egyptian rousette)
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
ray05212  Pancreatic cancer
ray05212

Organism
Rousettus aegyptiacus (Egyptian rousette) [GN:ray]
Gene
107497434  KRAS; GTPase KRas isoform X1 [KO:K07827]
107520152  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
107517828  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
107513958  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
107521668  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649]
107517899  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
107498704  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
107501389  ARHGEF6; rho guanine nucleotide exchange factor 6 isoform X1 [KO:K05729]
107515925  RAC1; ras-related C3 botulinum toxin substrate 1 isoform X1 [KO:K04392]
107519267  RAC2; ras-related C3 botulinum toxin substrate 2 [KO:K07860]
107520254  RAC3; ras-related C3 botulinum toxin substrate 3 [KO:K07861]
107517900  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
107497522  RELA; transcription factor p65 [KO:K04735]
107513978  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
107521783  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
107498395  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
107499756  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X1 [KO:K04467] [EC:2.7.11.10]
107501353  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
107499585  IKBKG; NF-kappa-B essential modulator isoform X1 [KO:K07210]
107497091  BAD; bcl2-associated agonist of cell death [KO:K02158]
107512887  BCL2L1; bcl-2-like protein 1 [KO:K04570]
107501830  CASP9; caspase-9 [KO:K04399] [EC:3.4.22.62]
107509353  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
107504052  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
107519729  RAF1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:2.7.11.1]
107508942  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
107515836  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
107497830  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
107512328  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
107509910  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
107515392  MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
107504584  RALGDS; ral guanine nucleotide dissociation stimulator isoform X1 [KO:K08732]
107512715  RALA; ras-related protein Ral-A [KO:K07834]
107501432  RALB; ras-related protein Ral-B [KO:K07835]
107498187  RALBP1; ralA-binding protein 1 isoform X1 [KO:K08773]
107513058  CDC42; cell division control protein 42 homolog isoform X1 [KO:K04393]
107515926  PLD1; phospholipase D1 [KO:K01115] [EC:3.1.4.4]
107509491  PLD2; phospholipase D2 isoform X1 [KO:K01115] [EC:3.1.4.4]
107519111  TGFA; protransforming growth factor alpha [KO:K08774]
107508819  EGF; pro-epidermal growth factor isoform X1 [KO:K04357]
107498193  EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
107520699  ERBB2; receptor tyrosine-protein kinase erbB-2 [KO:K05083] [EC:2.7.10.1]
107513109  MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
107503682  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
107510136  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
107517940  JAK1; tyrosine-protein kinase JAK1 [KO:K11217] [EC:2.7.10.2]
107513823  STAT3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
107519182  STAT1; LOW QUALITY PROTEIN: signal transducer and activator of transcription 1-alpha/beta [KO:K11220]
107502007  VEGFA; vascular endothelial growth factor A isoform X1 [KO:K05448]
107506789  cyclin-dependent kinase inhibitor 2A-like [KO:K06621]
107501504  CDK4; cyclin-dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
107519055  CDK6; cyclin-dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
107503391  CCND1; G1/S-specific cyclin-D1 [KO:K04503]
107520925  RB1; retinoblastoma-associated protein [KO:K06618]
107519491  E2F1; transcription factor E2F1 [KO:K17454]
107501037  E2F2; transcription factor E2F2 isoform X1 [KO:K09389]
107501692  E2F3; transcription factor E2F3 isoform X1 [KO:K06620]
107515689  TP53; cellular tumor antigen p53 isoform X1 [KO:K04451]
107514682  CDKN1A; cyclin-dependent kinase inhibitor 1 isoform X1 [KO:K06625]
107520573  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
107520147  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
107499083  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
107498831  BAX; apoptosis regulator BAX isoform X1 [KO:K02159]
107511968  BAK1; bcl-2 homologous antagonist/killer isoform X1 [KO:K14021]
107511851  DDB2; DNA damage-binding protein 2 isoform X1 [KO:K10140]
107506450  POLK; DNA polymerase kappa [KO:K03511] [EC:2.7.7.7]
107505490  TGFB1; transforming growth factor beta-1 [KO:K13375]
107520844  TGFB2; transforming growth factor beta-2 isoform X1 [KO:K13376]
107498899  TGFB3; transforming growth factor beta-3 [KO:K13377]
107500589  TGFBR1; TGF-beta receptor type-1 isoform X1 [KO:K04674] [EC:2.7.11.30]
107508791  TGFBR2; TGF-beta receptor type-2 [KO:K04388] [EC:2.7.11.30]
107512663  SMAD2; mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
107508935  SMAD3; mothers against decapentaplegic homolog 3 [KO:K23605]
107512852  SMAD4; mothers against decapentaplegic homolog 4 isoform X1 [KO:K04501]
107504798  BRCA2; breast cancer type 2 susceptibility protein isoform X1 [KO:K08775]
107514480  RAD51; DNA repair protein RAD51 homolog 1 isoform X1 [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
ray04010  MAPK signaling pathway
ray04012  ErbB signaling pathway
ray04110  Cell cycle
ray04115  p53 signaling pathway
ray04151  PI3K-Akt signaling pathway
ray04210  Apoptosis
ray04350  TGF-beta signaling pathway
ray04370  VEGF signaling pathway
ray04630  JAK-STAT signaling pathway
KO pathway
ko05212   
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