KEGG   PATHWAY: bacu05212
Entry
bacu05212                   Pathway                                
Name
Pancreatic cancer - Balaenoptera acutorostrata scammoni (minke 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
bacu05212  Pancreatic cancer
bacu05212

Organism
Balaenoptera acutorostrata scammoni (minke whale) [GN:bacu]
Gene
103015457  KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
103012691  PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
103012931  PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
103014043  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
103008077  PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
103009307  PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
103007464  PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
103012611  ARHGEF6; Rac/Cdc42 guanine nucleotide exchange factor 6 [KO:K05729]
103007995  RAC1; ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) [KO:K04392]
103006132  RAC2; ras-related C3 botulinum toxin substrate 2 (rho family, small GTP binding protein Rac2) [KO:K07860]
103019253  RAC3; ras-related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3) [KO:K07861]
102999230  NFKB1; nuclear factor kappa B subunit 1 [KO:K02580]
103019614  RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735]
103002026  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
103013147  AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]
103004139  AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]
103015414  CHUK; conserved helix-loop-helix ubiquitous kinase [KO:K04467] [EC:2.7.11.10]
103015119  IKBKB; inhibitor of nuclear factor kappa B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
103017855  NF-kappa-B essential modulator-like [KO:K07210]
103005702  BAD; BCL2 associated agonist of cell death [KO:K02158]
103017903  BCL2L1; BCL2 like 1 [KO:K04570]
103010071  CASP9; caspase 9 [KO:K04399] [EC:3.4.22.62]
103020975  ARAF; A-Raf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:2.7.11.1]
103002372  BRAF; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:2.7.11.1]
103014337  RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
103017381  MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
102999619  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
103002590  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
102997603  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
103007019  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
103008728  MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
103008135  RALGDS; ral guanine nucleotide dissociation stimulator [KO:K08732]
103013487  RALA; RAS like proto-oncogene A [KO:K07834]
103003598  RALB; RAS like proto-oncogene B [KO:K07835]
103020492  RALBP1; ralA binding protein 1 [KO:K08773]
103008817  CDC42; cell division cycle 42 [KO:K04393]
103008865  PLD2; phospholipase D2 [KO:K01115] [EC:3.1.4.4]
102999715  PLD1; phospholipase D1 [KO:K01115] [EC:3.1.4.4]
103010563  TGFA; transforming growth factor alpha [KO:K08774]
103004366  EGF; epidermal growth factor [KO:K04357]
103017029  EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
103002640  ERBB2; erb-b2 receptor tyrosine kinase 2 [KO:K05083] [EC:2.7.10.1]
103004460  MTOR; mechanistic target of rapamycin [KO:K07203] [EC:2.7.11.1]
103019799  RPS6KB1; ribosomal protein S6 kinase B1 [KO:K04688] [EC:2.7.11.1]
102998750  RPS6KB2; ribosomal protein S6 kinase B2 [KO:K04688] [EC:2.7.11.1]
103004050  JAK1; Janus kinase 1 [KO:K11217] [EC:2.7.10.2]
102997405  signal transducer and activator of transcription 3-like [KO:K04692]
103008157  STAT3; signal transducer and activator of transcription 3 (acute-phase response factor) [KO:K04692]
103013781  signal transducer and activator of transcription 1-like [KO:K11220]
103008131  VEGFA; vascular endothelial growth factor A [KO:K05448]
103012968  CDKN2A; cyclin dependent kinase inhibitor 2A [KO:K06621]
103000540  CDK4; cyclin dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
103010593  cyclin-dependent kinase 4-like [KO:K02089] [EC:2.7.11.22]
103011327  CDK6; cyclin dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
103013404  CCND1; cyclin D1 [KO:K04503]
103013752  RB1; RB transcriptional corepressor 1 [KO:K06618]
103015828  E2F1; E2F transcription factor 1 [KO:K17454]
103017714  E2F2; E2F transcription factor 2 [KO:K09389]
103007760  E2F3; E2F transcription factor 3 [KO:K06620]
103003426  TP53; tumor protein p53 [KO:K04451]
103005082  CDKN1A; cyclin dependent kinase inhibitor 1A [KO:K06625]
103012188  GADD45G; growth arrest and DNA damage inducible gamma [KO:K04402]
103016967  GADD45B; growth arrest and DNA damage inducible beta [KO:K04402]
103020367  GADD45A; growth arrest and DNA damage inducible alpha [KO:K04402]
103019528  BAX; BCL2 associated X, apoptosis regulator [KO:K02159]
102999845  putative Bcl-2 homologous antagonist/killer 2-like [KO:K14021]
103017537  DDB2; damage specific DNA binding protein 2 [KO:K10140]
103009875  POLK; DNA polymerase kappa [KO:K03511] [EC:2.7.7.7]
103002687  TGFB1; transforming growth factor beta 1 [KO:K13375]
103001453  TGFB2; transforming growth factor beta 2 [KO:K13376]
103001029  TGFB3; transforming growth factor beta 3 [KO:K13377]
102999446  TGFBR1; transforming growth factor beta receptor 1 [KO:K04674] [EC:2.7.11.30]
103005777  TGFBR2; transforming growth factor beta receptor 2 [KO:K04388] [EC:2.7.11.30]
103005078  SMAD2; SMAD family member 2 [KO:K04500]
103019152  SMAD3; SMAD family member 3 [KO:K23605]
103014916  SMAD4; SMAD family member 4 [KO:K04501]
103017905  BRCA2; BRCA2, DNA repair associated [KO:K08775]
103013823  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
  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
bacu04010  MAPK signaling pathway
bacu04012  ErbB signaling pathway
bacu04110  Cell cycle
bacu04115  p53 signaling pathway
bacu04151  PI3K-Akt signaling pathway
bacu04210  Apoptosis
bacu04350  TGF-beta signaling pathway
bacu04370  VEGF signaling pathway
bacu04630  JAK-STAT signaling pathway
KO pathway
ko05212   
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