KEGG   PATHWAY: elk05212
Entry
elk05212                    Pathway                                

Name
Pancreatic cancer - Enhydra lutris kenyoni (northern sea otter)
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
elk05212  Pancreatic cancer
elk05212

Organism
Enhydra lutris kenyoni (northern sea otter) [GN:elk]
Gene
111159984  GTPase KRas isoform X1 [KO:K07827]
111155003  LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
111147545  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
111154641  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
111143470  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
111155224  phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
111143790  phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
111139338  rho guanine nucleotide exchange factor 6 isoform X1 [KO:K05729]
111145636  ras-related C3 botulinum toxin substrate 1 isoform X1 [KO:K04392]
111157484  ras-related C3 botulinum toxin substrate 2 [KO:K07860]
111160304  ras-related C3 botulinum toxin substrate 3 isoform X1 [KO:K07861]
111153611  nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
111149956  transcription factor p65 [KO:K04735]
111161374  RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
111148765  RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
111150885  RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
111144921  inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X1 [KO:K04467] [EC:2.7.11.10]
111144397  inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
111139191  NF-kappa-B essential modulator [KO:K07210]
111149975  bcl2-associated agonist of cell death [KO:K02158]
111141775  bcl-2-like protein 1 [KO:K04570]
111154673  caspase-9 isoform X1 [KO:K04399] [EC:3.4.22.62]
111150582  serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
111151941  serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
111144322  RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
111153158  dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
111162236  LOW QUALITY PROTEIN: mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
111142759  mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
111144860  mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
111158897  mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
111154016  mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
111145587  ral guanine nucleotide dissociation stimulator isoform X1 [KO:K08732]
111157020  ras-related protein Ral-A [KO:K07834]
111141953  ras-related protein Ral-B [KO:K07835]
111142686  ralA-binding protein 1 [KO:K08773]
111154823  cell division control protein 42 homolog isoform X1 [KO:K04393]
111161193  phospholipase D2 [KO:K01115] [EC:3.1.4.4]
111150121  phospholipase D1 isoform X1 [KO:K01115] [EC:3.1.4.4]
111148116  protransforming growth factor alpha [KO:K08774]
111156359  pro-epidermal growth factor isoform X1 [KO:K04357]
111157042  epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
111151268  receptor tyrosine-protein kinase erbB-2 isoform X1 [KO:K05083] [EC:2.7.10.1]
111154883  serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
111149588  ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
111151757  ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
111142881  tyrosine-protein kinase JAK1 [KO:K11217] [EC:2.7.10.2]
111151241  signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
111144592  signal transducer and activator of transcription 1-alpha/beta isoform X1 [KO:K11220]
111147726  vascular endothelial growth factor A [KO:K05448]
111159871  cyclin-dependent kinase inhibitor 2A-like isoform X1 [KO:K06621]
111160230  cyclin-dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
111147246  cyclin-dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
111149458  G1/S-specific cyclin-D1 [KO:K04503]
111146911  retinoblastoma-associated protein [KO:K06618]
111141556  transcription factor E2F1 [KO:K17454]
111154729  transcription factor E2F2 isoform X1 [KO:K09389]
111138625  transcription factor E2F3 isoform X1 [KO:K06620]
111161133  cellular tumor antigen p53 [KO:K04451]
111147618  cyclin-dependent kinase inhibitor 1 [KO:K06625]
111143201  growth arrest and DNA damage-inducible protein GADD45 alpha isoform X1 [KO:K04402]
111161789  growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
111153625  growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
111160657  apoptosis regulator BAX isoform X1 [KO:K02159]
111152355  bcl-2 homologous antagonist/killer [KO:K14021]
111150113  DNA damage-binding protein 2 isoform X1 [KO:K10140]
111148313  DNA polymerase kappa [KO:K03511] [EC:2.7.7.7]
111161420  transforming growth factor beta-1 isoform X1 [KO:K13375]
111151068  transforming growth factor beta-2 isoform X1 [KO:K13376]
111148592  transforming growth factor beta-3 [KO:K13377]
111146071  TGF-beta receptor type-1 isoform X1 [KO:K04674] [EC:2.7.11.30]
111158999  TGF-beta receptor type-2 [KO:K04388] [EC:2.7.11.30]
111142395  mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
111153179  mothers against decapentaplegic homolog 3 [KO:K23605]
111142438  mothers against decapentaplegic homolog 4 [KO:K04501]
111158584  breast cancer type 2 susceptibility protein [KO:K08775]
111159884  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
elk04010  MAPK signaling pathway
elk04012  ErbB signaling pathway
elk04110  Cell cycle
elk04115  p53 signaling pathway
elk04151  PI3K-Akt signaling pathway
elk04210  Apoptosis
elk04350  TGF-beta signaling pathway
elk04370  VEGF signaling pathway
elk04630  JAK-STAT signaling pathway
KO pathway
ko05212   
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