KEGG   PATHWAY: pcad05212
Entry
pcad05212                   Pathway                                

Name
Pancreatic cancer - Physeter catodon (sperm 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
pcad05212  Pancreatic cancer
pcad05212

Organism
Physeter catodon (sperm whale) [GN:pcad]
Gene
102977125  KRAS; GTPase KRas isoform X2 [KO:K07827]
102986098  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
102978952  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
102977108  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
102975555  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
102991779  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
102991192  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X2 [KO:K02649]
102974344  ARHGEF6; rho guanine nucleotide exchange factor 6 isoform X1 [KO:K05729]
102979195  rho-related BTB domain-containing protein 2 [KO:K04392]
102990276  RAC1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]
102990552  RAC2; ras-related C3 botulinum toxin substrate 2 isoform X1 [KO:K07860]
102992553  RAC3; ras-related C3 botulinum toxin substrate 3 isoform X1 [KO:K07861]
102981135  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
102974198  RELA; transcription factor p65 isoform X2 [KO:K04735]
102981524  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
102976971  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
102990087  RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
102977668  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X2 [KO:K04467] [EC:2.7.11.10]
102976706  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
114485485  NF-kappa-B essential modulator-like isoform X1 [KO:K07210]
102980964  IKBKG; NF-kappa-B essential modulator [KO:K07210]
102974655  BAD; bcl2-associated agonist of cell death [KO:K02158]
102980439  BCL2L1; bcl-2-like protein 1 isoform X1 [KO:K04570]
102989458  CASP9; caspase-9 isoform X1 [KO:K04399] [EC:3.4.22.62]
102974274  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
102986916  BRAF; serine/threonine-protein kinase B-raf isoform X3 [KO:K04365] [EC:2.7.11.1]
102987866  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X2 [KO:K04366] [EC:2.7.11.1]
102992191  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
102984305  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
102989074  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
102996353  MAPK8; mitogen-activated protein kinase 8 isoform X3 [KO:K04440] [EC:2.7.11.24]
102977417  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
102984741  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
102992808  RALGDS; ral guanine nucleotide dissociation stimulator isoform X5 [KO:K08732]
102987577  RALA; ras-related protein Ral-A [KO:K07834]
102979041  RALB; ras-related protein Ral-B [KO:K07835]
102994813  RALBP1; ralA-binding protein 1 isoform X1 [KO:K08773]
102975958  CDC42; cell division control protein 42 homolog isoform X1 [KO:K04393]
102978946  PLD2; phospholipase D2 [KO:K01115] [EC:3.1.4.4]
102986218  PLD1; phospholipase D1 isoform X1 [KO:K01115] [EC:3.1.4.4]
102973542  TGFA; protransforming growth factor alpha isoform X1 [KO:K08774]
102977431  EGF; pro-epidermal growth factor isoform X1 [KO:K04357]
102975467  EGFR; epidermal growth factor receptor isoform X3 [KO:K04361] [EC:2.7.10.1]
102990192  ERBB2; receptor tyrosine-protein kinase erbB-2 isoform X1 [KO:K05083] [EC:2.7.10.1]
102991493  MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
102976885  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
102990399  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
102988182  JAK1; tyrosine-protein kinase JAK1 [KO:K11217] [EC:2.7.10.2]
102976764  STAT3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
102977655  STAT1; signal transducer and activator of transcription 1-alpha/beta isoform X1 [KO:K11220]
102981739  VEGFA; vascular endothelial growth factor A isoform X5 [KO:K05448]
102984840  cyclin-dependent kinase inhibitor 2A-like isoform X1 [KO:K06621]
102985179  CDK4; cyclin-dependent kinase 4 isoform X1 [KO:K02089] [EC:2.7.11.22]
102992532  CDK6; cyclin-dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
102996914  CCND1; G1/S-specific cyclin-D1 [KO:K04503]
102995201  RB1; retinoblastoma-associated protein isoform X1 [KO:K06618]
102993481  E2F1; transcription factor E2F1 isoform X1 [KO:K17454]
102996979  transcription factor E2F2 [KO:K09389]
102976146  E2F3; transcription factor E2F3 isoform X1 [KO:K06620]
102985658  TP53; cellular tumor antigen p53 [KO:K04451]
102995437  CDKN1A; cyclin-dependent kinase inhibitor 1 [KO:K06625]
102974987  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
102993403  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
102986518  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
102991092  BAK1; bcl-2 homologous antagonist/killer [KO:K14021]
102974256  DDB2; DNA damage-binding protein 2 isoform X1 [KO:K10140]
102976634  POLK; DNA polymerase kappa isoform X1 [KO:K03511] [EC:2.7.7.7]
102975643  TGFB1; transforming growth factor beta-1 proprotein isoform X1 [KO:K13375]
102993033  TGFB2; transforming growth factor beta-2 proprotein isoform X1 [KO:K13376]
102977345  TGFB3; transforming growth factor beta-3 proprotein [KO:K13377]
102978050  TGFBR1; TGF-beta receptor type-1 isoform X1 [KO:K04674] [EC:2.7.11.30]
102995949  TGFBR2; TGF-beta receptor type-2 isoform X1 [KO:K04388] [EC:2.7.11.30]
102978015  SMAD2; mothers against decapentaplegic homolog 2 [KO:K04500]
102989819  SMAD3; mothers against decapentaplegic homolog 3 isoform X2 [KO:K23605]
102986517  SMAD4; mothers against decapentaplegic homolog 4 [KO:K04501]
102995983  BRCA2; LOW QUALITY PROTEIN: breast cancer type 2 susceptibility protein [KO:K08775]
102989193  RAD51; 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
pcad04010  MAPK signaling pathway
pcad04012  ErbB signaling pathway
pcad04110  Cell cycle
pcad04115  p53 signaling pathway
pcad04151  PI3K-Akt signaling pathway
pcad04210  Apoptosis
pcad04350  TGF-beta signaling pathway
pcad04370  VEGF signaling pathway
pcad04630  JAK-STAT signaling pathway
KO pathway
ko05212   
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