KEGG   PATHWAY: lav05212
Entry
lav05212                    Pathway                                

Name
Pancreatic cancer - Loxodonta africana (African savanna elephant)
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
lav05212  Pancreatic cancer
lav05212

Organism
Loxodonta africana (African savanna elephant) [GN:lav]
Gene
100661512  KRAS; GTPase KRas isoform X2 [KO:K07827]
100657948  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
100658340  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100666266  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
100653731  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
100665045  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
100675496  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
100658524  ARHGEF6; rho guanine nucleotide exchange factor 6 isoform X1 [KO:K05729]
100664204  RAC1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]
100670080  RAC2; ras-related C3 botulinum toxin substrate 2 [KO:K07860]
100662194  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
100654730  RELA; transcription factor p65 isoform X2 [KO:K04735]
100663184  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
100657536  AKT3; RAC-gamma serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
100660187  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100664361  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X1 [KO:K04467] [EC:2.7.11.10]
100657363  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X3 [KO:K07209] [EC:2.7.11.10]
100661492  IKBKG; LOW QUALITY PROTEIN: NF-kappa-B essential modulator [KO:K07210]
100668387  BAD; bcl2-associated agonist of cell death [KO:K02158]
100655646  BCL2L1; bcl-2-like protein 1 isoform X1 [KO:K04570]
100656597  CASP9; caspase-9 isoform X3 [KO:K04399] [EC:3.4.22.62]
100671404  ARAF; serine/threonine-protein kinase A-Raf isoform X3 [KO:K08845] [EC:2.7.11.1]
100664119  BRAF; serine/threonine-protein kinase B-raf [KO:K04365] [EC:2.7.11.1]
100655727  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
100667623  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
100658240  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
100665157  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
100654943  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
100674229  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
100673395  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
100659236  RALGDS; ral guanine nucleotide dissociation stimulator isoform X1 [KO:K08732]
100674091  LOW QUALITY PROTEIN: ral guanine nucleotide dissociation stimulator-like [KO:K08732]
100662460  RALA; ras-related protein Ral-A [KO:K07834]
100669974  RALB; ras-related protein Ral-B [KO:K07835]
100674030  RALBP1; ralA-binding protein 1 [KO:K08773]
100664103  CDC42; cell division control protein 42 homolog [KO:K04393]
100660595  PLD1; phospholipase D1 isoform X2 [KO:K01115] [EC:3.1.4.4]
100658318  PLD2; LOW QUALITY PROTEIN: phospholipase D2 [KO:K01115] [EC:3.1.4.4]
100665332  TGFA; protransforming growth factor alpha [KO:K08774]
100670137  EGF; LOW QUALITY PROTEIN: pro-epidermal growth factor [KO:K04357]
100659125  EGFR; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
100662583  ERBB2; receptor tyrosine-protein kinase erbB-2 isoform X2 [KO:K05083] [EC:2.7.10.1]
100660112  MTOR; LOW QUALITY PROTEIN: serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
100653946  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
100671034  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
100655548  JAK1; tyrosine-protein kinase JAK1 [KO:K11217] [EC:2.7.10.2]
100669583  STAT3; signal transducer and activator of transcription 3 isoform X2 [KO:K04692]
100668424  STAT1; signal transducer and activator of transcription 1-alpha/beta [KO:K11220]
100661392  VEGFA; vascular endothelial growth factor A [KO:K05448]
104845647  cyclin-dependent kinase inhibitor 2A-like [KO:K06621]
104847103  CDK4; cyclin-dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
100655429  CDK6; cyclin-dependent kinase 6 isoform X1 [KO:K02091] [EC:2.7.11.22]
100669703  CCND1; G1/S-specific cyclin-D1 [KO:K04503]
100673196  RB1; retinoblastoma-associated protein [KO:K06618]
100664468  E2F1; LOW QUALITY PROTEIN: transcription factor E2F1 [KO:K17454]
100665816  E2F2; transcription factor E2F2 isoform X1 [KO:K09389]
100656140  E2F3; transcription factor E2F3 isoform X1 [KO:K06620]
100663725  TP53; cellular tumor antigen p53 isoform X1 [KO:K04451]
100671706  CDKN1A; cyclin-dependent kinase inhibitor 1 [KO:K06625]
100658253  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
100655692  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta isoform X2 [KO:K04402]
100653562  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
100673560  BAX; apoptosis regulator BAX [KO:K02159]
100669799  BAK1; bcl-2 homologous antagonist/killer [KO:K14021]
100665802  DDB2; DNA damage-binding protein 2 isoform X1 [KO:K10140]
100662275  POLK; DNA polymerase kappa isoform X2 [KO:K03511] [EC:2.7.7.7]
100667634  TGFB1; transforming growth factor beta-1 [KO:K13375]
100656534  TGFB2; transforming growth factor beta-2 isoform X2 [KO:K13376]
100653832  TGFB3; transforming growth factor beta-3 isoform X1 [KO:K13377]
100656286  TGFBR1; TGF-beta receptor type-1 isoform X1 [KO:K04674] [EC:2.7.11.30]
100671392  TGFBR2; TGF-beta receptor type-2 isoform X2 [KO:K04388] [EC:2.7.11.30]
100663495  SMAD2; mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
100659509  SMAD4; mothers against decapentaplegic homolog 4 [KO:K04501]
100669658  BRCA2; LOW QUALITY PROTEIN: breast cancer type 2 susceptibility protein [KO:K08775]
100662321  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
lav04010  MAPK signaling pathway
lav04012  ErbB signaling pathway
lav04110  Cell cycle
lav04115  p53 signaling pathway
lav04151  PI3K-Akt signaling pathway
lav04210  Apoptosis
lav04350  TGF-beta signaling pathway
lav04370  VEGF signaling pathway
lav04630  JAK-STAT signaling pathway
KO pathway
ko05212   
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