KEGG   PATHWAY: elk05212
elk05212                    Pathway                                

Pancreatic cancer - Enhydra lutris kenyoni (northern sea otter)
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.
Human Diseases; Cancer: specific types
Pathway map
elk05212  Pancreatic cancer

Enhydra lutris kenyoni (northern sea otter) [GN:elk]
111159984  GTPase KRas isoform X1 [KO:K07827]
111155003  LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:]
111147545  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:]
111154641  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:]
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:]
111148765  RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:]
111150885  RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:]
111144921  inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X1 [KO:K04467] [EC:]
111144397  inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:]
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:]
111150582  serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:]
111151941  serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:]
111144322  RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:]
111153158  dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:]
111162236  LOW QUALITY PROTEIN: mitogen-activated protein kinase 3 [KO:K04371] [EC:]
111142759  mitogen-activated protein kinase 1 [KO:K04371] [EC:]
111144860  mitogen-activated protein kinase 8 [KO:K04440] [EC:]
111158897  mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:]
111154016  mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:]
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:]
111150121  phospholipase D1 isoform X1 [KO:K01115] [EC:]
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:]
111151268  receptor tyrosine-protein kinase erbB-2 isoform X1 [KO:K05083] [EC:]
111154883  serine/threonine-protein kinase mTOR [KO:K07203] [EC:]
111149588  ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:]
111151757  ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:]
111142881  tyrosine-protein kinase JAK1 [KO:K11217] [EC:]
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:]
111147246  cyclin-dependent kinase 6 [KO:K02091] [EC:]
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:]
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:]
111158999  TGF-beta receptor type-2 [KO:K04388] [EC:]
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]
C00416  Phosphatidate
C05981  Phosphatidylinositol-3,4,5-trisphosphate
Von Hoff D, Evans D, Hruban R (ed).
Pancreatic cancer
Jones and Bartlett publishers (2005)
Niitsu Y, Yokota J (ed).
[Oncogenes and Tumor Suppressor Genes for Medical Oncologist] (In Japanese)
Nankodo (1999)
Bardeesy N, DePinho RA.
Pancreatic cancer biology and genetics.
Nat Rev Cancer 2:897-909 (2002)
Bardeesy N, Sharpless NE, DePinho RA, Merlino G.
The genetics of pancreatic adenocarcinoma: a roadmap for a mouse model.
Semin Cancer Biol 11:201-18 (2001)
Cowgill SM, Muscarella P.
The genetics of pancreatic cancer.
Am J Surg 186:279-86 (2003)
Hezel AF, Kimmelman AC, Stanger BZ, Bardeesy N, Depinho RA.
Genetics and biology of pancreatic ductal adenocarcinoma.
Genes Dev 20:1218-49 (2006)
Shields JM, Pruitt K, McFall A, Shaub A, Der CJ.
Understanding Ras: 'it ain't over 'til it's over'.
Trends Cell Biol 10:147-54 (2000)
Holbro T, Civenni G, Hynes NE.
The ErbB receptors and their role in cancer progression.
Exp Cell Res 284:99-110 (2003)
Marmor MD, Skaria KB, Yarden Y.
Signal transduction and oncogenesis by ErbB/HER receptors.
Int J Radiat Oncol Biol Phys 58:903-13 (2004)
DeArmond D, Brattain MG, Jessup JM, Kreisberg J, Malik S, Zhao S, Freeman JW.
Autocrine-mediated ErbB-2 kinase activation of STAT3 is required for growth factor independence of pancreatic cancer cell lines.
Oncogene 22:7781-95 (2003)
Wei D, Le X, Zheng L, Wang L, Frey JA, Gao AC, Peng Z, Huang S, Xiong HQ, Abbruzzese JL, Xie K.
Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis.
Oncogene 22:319-29 (2003)
Toyonaga T, Nakano K, Nagano M, Zhao G, Yamaguchi K, Kuroki S, Eguchi T, Chijiiwa K, Tsuneyoshi M, Tanaka M.
Blockade of constitutively activated Janus kinase/signal transducer and activator of transcription-3 pathway inhibits growth of human pancreatic cancer.
Cancer Lett 201:107-16 (2003)
Schmid RM.
Genetic basis of pancreatic cancer.
Best Pract Res Clin Gastroenterol 16:421-33 (2002)
Elliott RL, Blobe GC.
Role of transforming growth factor Beta in human cancer.
J Clin Oncol 23:2078-93 (2005)
Rudkin TM, Foulkes WD.
BRCA2: breaks, mistakes and failed separations.
Trends Mol Med 11:145-8 (2005)
Venkitaraman AR.
Functions of BRCA1 and BRCA2 in the biological response to DNA damage.
J Cell Sci 114:3591-8 (2001)
Chang Z, Li Z, Wang X, Kang Y, Yuan Y, Niu J, Wang H, Chatterjee D, Fleming JB, Li M, Abbruzzese JL, Chiao PJ
Deciphering the mechanisms of tumorigenesis in human pancreatic ductal epithelial cells.
Clin Cancer Res 19:549-59 (2013)
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

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