KEGG   PATHWAY: rro05212
Entry
rro05212                    Pathway                                

Name
Pancreatic cancer - Rhinopithecus roxellana (golden snub-nosed monkey)
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
rro05212  Pancreatic cancer
rro05212

Organism
Rhinopithecus roxellana (golden snub-nosed monkey) [GN:rro]
Gene
104670041  KRAS; GTPase KRas isoform X1 [KO:K07827]
104663050  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
104665061  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
104670605  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
104662124  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
104675620  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
104680672  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
104682443  ARHGEF6; rho guanine nucleotide exchange factor 6 isoform X1 [KO:K05729]
104665823  RAC1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]
104682502  RAC2; ras-related C3 botulinum toxin substrate 2 [KO:K07860]
104654979  RAC3; ras-related C3 botulinum toxin substrate 3 isoform X1 [KO:K07861]
104662315  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
104664815  RELA; transcription factor p65 [KO:K04735]
104673041  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
104676121  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
104654186  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
115893905  RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
104656469  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X1 [KO:K04467] [EC:2.7.11.10]
104666046  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X2 [KO:K07209] [EC:2.7.11.10]
104667046  IKBKG; NF-kappa-B essential modulator isoform X1 [KO:K07210]
104673141  BAD; bcl2-associated agonist of cell death [KO:K02158]
104653720  BCL2L1; bcl-2-like protein 1 isoform X1 [KO:K04570]
104677696  CASP9; caspase-9 isoform X1 [KO:K04399] [EC:3.4.22.62]
104664593  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
104659700  BRAF; serine/threonine-protein kinase B-raf isoform X2 [KO:K04365] [EC:2.7.11.1]
104673299  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X2 [KO:K04366] [EC:2.7.11.1]
104662575  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
104676897  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
104681150  MAPK3; LOW QUALITY PROTEIN: mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
104676194  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
104678447  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
104668007  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
104669737  RALGDS; ral guanine nucleotide dissociation stimulator isoform X2 [KO:K08732]
104674726  ral-GDS-related protein-like [KO:K08732]
104663117  RALA; ras-related protein Ral-A [KO:K07834]
104672611  RALB; ras-related protein Ral-B [KO:K07835]
104670235  RALBP1; ralA-binding protein 1 [KO:K08773]
104663221  CDC42; cell division control protein 42 homolog [KO:K04393]
104666985  PLD1; phospholipase D1 isoform X1 [KO:K01115] [EC:3.1.4.4]
104663087  PLD2; phospholipase D2 [KO:K01115] [EC:3.1.4.4]
104661322  TGFA; protransforming growth factor alpha isoform X1 [KO:K08774]
104682421  EGF; pro-epidermal growth factor isoform X1 [KO:K04357]
104675886  EGFR; LOW QUALITY PROTEIN: epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
104674848  ERBB2; receptor tyrosine-protein kinase erbB-2 [KO:K05083] [EC:2.7.10.1]
104654362  MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
104662932  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
104664740  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
104668074  JAK1; tyrosine-protein kinase JAK1 isoform X1 [KO:K11217] [EC:2.7.10.2]
104680286  STAT3; signal transducer and activator of transcription 3 isoform X3 [KO:K04692]
104675282  STAT1; signal transducer and activator of transcription 1-alpha/beta [KO:K11220]
104667362  VEGFA; vascular endothelial growth factor A isoform X1 [KO:K05448]
104654275  CDKN2A; cyclin-dependent kinase inhibitor 2A isoform X1 [KO:K06621]
104682344  CDK4; cyclin-dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
104682750  CDK6; cyclin-dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
104677168  CCND1; G1/S-specific cyclin-D1 [KO:K04503]
104662760  RB1; retinoblastoma-associated protein [KO:K06618]
104660298  E2F1; transcription factor E2F1 [KO:K17454]
104656129  E2F2; LOW QUALITY PROTEIN: transcription factor E2F2 [KO:K09389]
104654803  E2F3; transcription factor E2F3 isoform X1 [KO:K06620]
104661662  TP53; cellular tumor antigen p53 [KO:K04451]
104682880  CDKN1A; cyclin-dependent kinase inhibitor 1 [KO:K06625]
104671382  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
104657306  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
104656307  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
104666540  BAX; apoptosis regulator BAX isoform X1 [KO:K02159]
104658958  BAK1; bcl-2 homologous antagonist/killer [KO:K14021]
104668405  DDB2; DNA damage-binding protein 2 [KO:K10140]
104653753  POLK; DNA polymerase kappa isoform X1 [KO:K03511] [EC:2.7.7.7]
104676086  TGFB1; transforming growth factor beta-1 proprotein isoform X2 [KO:K13375]
104662252  TGFB2; transforming growth factor beta-2 proprotein isoform X1 [KO:K13376]
104677599  TGFB3; transforming growth factor beta-3 proprotein isoform X1 [KO:K13377]
104657765  TGFBR1; TGF-beta receptor type-1 isoform X1 [KO:K04674] [EC:2.7.11.30]
104655082  TGFBR2; TGF-beta receptor type-2 isoform X1 [KO:K04388] [EC:2.7.11.30]
104662580  SMAD3; mothers against decapentaplegic homolog 3 isoform X2 [KO:K23605]
104672916  SMAD4; mothers against decapentaplegic homolog 4 [KO:K04501]
104665294  BRCA2; breast cancer type 2 susceptibility protein isoform X2 [KO:K08775]
104682060  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
rro04010  MAPK signaling pathway
rro04012  ErbB signaling pathway
rro04110  Cell cycle
rro04115  p53 signaling pathway
rro04151  PI3K-Akt signaling pathway
rro04210  Apoptosis
rro04350  TGF-beta signaling pathway
rro04370  VEGF signaling pathway
rro04630  JAK-STAT signaling pathway
KO pathway
ko05212   
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