KEGG   PATHWAY: ppam05212
Entry
ppam05212                   Pathway                                
Name
Pancreatic cancer - Pteronotus mesoamericanus (Parnell's mustached bat)
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
ppam05212  Pancreatic cancer
ppam05212

Organism
Pteronotus mesoamericanus (Parnell's mustached bat) [GN:ppam]
Gene
129084969  KRAS; GTPase KRas isoform X1 [KO:K07827]
129075675  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
129076577  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
129088291  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
129074969  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
129069407  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
129074590  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
129075479  ARHGEF6; rho guanine nucleotide exchange factor 6 isoform X1 [KO:K05729]
129078413  ras-related C3 botulinum toxin substrate 1-like [KO:K04392]
129068140  RAC1; ras-related C3 botulinum toxin substrate 1 isoform X1 [KO:K04392]
129071250  RAC2; ras-related C3 botulinum toxin substrate 2 [KO:K07860]
129086649  RAC3; ras-related C3 botulinum toxin substrate 3 isoform X1 [KO:K07861]
129085322  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
129068571  RELA; transcription factor p65 [KO:K04735]
129076641  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
129066231  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
129073033  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
129077110  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X1 [KO:K04467] [EC:2.7.11.10]
129064790  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
129074378  IKBKG; NF-kappa-B essential modulator [KO:K07210]
129068612  BAD; bcl2-associated agonist of cell death [KO:K02158]
129070790  BCL2L1; bcl-2-like protein 1 isoform X1 [KO:K04570]
129075586  CASP9; caspase-9 [KO:K04399] [EC:3.4.22.62]
129065223  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
129062984  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
129088423  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
129064157  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
129078069  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
129086248  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
129069687  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
129065007  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
129085376  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
129079186  RALGDS; ral guanine nucleotide dissociation stimulator isoform X1 [KO:K08732]
129063346  RALA; ras-related protein Ral-A [KO:K07834]
129071736  RALB; ras-related protein Ral-B isoform X1 [KO:K07835]
129081678  RALBP1; ralA-binding protein 1 [KO:K08773]
129069153  CDC42; cell division control protein 42 homolog isoform X1 [KO:K04393]
129076361  PLD1; phospholipase D1 isoform X1 [KO:K01115] [EC:3.1.4.4]
129072342  PLD2; phospholipase D2 [KO:K01115] [EC:3.1.4.4]
129081363  TGFA; protransforming growth factor alpha [KO:K08774]
129085287  EGF; pro-epidermal growth factor isoform X1 [KO:K04357]
129068919  EGFR; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
129087036  ERBB2; receptor tyrosine-protein kinase erbB-2 [KO:K05083] [EC:2.7.10.1]
129075656  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
129068535  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
129071563  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
129071023  JAK1; tyrosine-protein kinase JAK1 [KO:K11217] [EC:2.7.10.2]
129086937  STAT3; signal transducer and activator of transcription 3 isoform X1 [KO:K04692]
129065467  STAT1; signal transducer and activator of transcription 1-alpha/beta isoform X1 [KO:K11220]
129067485  VEGFA; vascular endothelial growth factor A [KO:K05448]
129075823  CDK4; cyclin-dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
129063507  CDK6; cyclin-dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
129068523  CCND1; G1/S-specific cyclin-D1 [KO:K04503]
129080865  RB1; retinoblastoma-associated protein isoform X1 [KO:K06618]
129070474  E2F1; transcription factor E2F1 [KO:K17454]
129068981  E2F2; transcription factor E2F2 [KO:K09389]
129085787  E2F3; transcription factor E2F3 [KO:K06620]
129072290  TP53; cellular tumor antigen p53 [KO:K04451]
129067419  CDKN1A; cyclin-dependent kinase inhibitor 1 [KO:K06625]
129082291  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
129069921  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
129081112  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
129082924  BAX; apoptosis regulator BAX [KO:K02159]
129066993  BAK1; bcl-2 homologous antagonist/killer [KO:K14021]
129081434  DDB2; DNA damage-binding protein 2 [KO:K10140]
129074622  POLK; DNA polymerase kappa isoform X1 [KO:K03511] [EC:2.7.7.7]
129076675  TGFB1; transforming growth factor beta-1 proprotein [KO:K13375]
129072973  TGFB2; transforming growth factor beta-2 proprotein isoform X1 [KO:K13376]
129065729  TGFB3; transforming growth factor beta-3 proprotein [KO:K13377]
129079398  TGFBR1; TGF-beta receptor type-1 [KO:K04674] [EC:2.7.11.30]
129088202  TGFBR2; TGF-beta receptor type-2 [KO:K04388] [EC:2.7.11.30]
129078704  SMAD2; mothers against decapentaplegic homolog 2 [KO:K04500]
129064154  SMAD3; mothers against decapentaplegic homolog 3 [KO:K23605]
129078725  SMAD4; mothers against decapentaplegic homolog 4 [KO:K04501]
129073786  BRCA2; breast cancer type 2 susceptibility protein [KO:K08775]
129064062  RAD51; DNA repair protein RAD51 homolog 1 isoform X1 [KO:K04482]
129064800  DNA repair protein RAD51 homolog 1-like 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
  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
ppam04010  MAPK signaling pathway
ppam04012  ErbB signaling pathway
ppam04110  Cell cycle
ppam04115  p53 signaling pathway
ppam04151  PI3K-Akt signaling pathway
ppam04210  Apoptosis
ppam04350  TGF-beta signaling pathway
ppam04370  VEGF signaling pathway
ppam04630  JAK-STAT signaling pathway
KO pathway
ko05212   
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