KEGG PATHWAY: rno05212

PATHWAY: rno05212

Entry

rno05212                    Pathway

Name

Pancreatic cancer - Rattus norvegicus (rat)

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

rno05212

Pancreatic cancer

Disease

H00019

Pancreatic cancer

Organism

Rattus norvegicus (rat) [GN:rno]

Gene

100362121

Ddb2; DNA damage-binding protein 2 [KO:K10140]

114483

Cdk6; cyclin-dependent kinase 6 [KO:K02091] [EC:2.7.11.22]

114486

Braf; serine/threonine-protein kinase B-raf isoform X2 [KO:K04365] [EC:2.7.11.1]

114851

Cdkn1a; cyclin-dependent kinase inhibitor 1 [KO:K06625]

116502

Bak1; bcl-2 homologous antagonist/killer [KO:K14021]

116546

Ralb; ras-related protein Ral-B [KO:K07835]

116554

Mapk8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]

116590

Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]

134484121

[KO:K00922] [EC:2.7.1.153]

170851

Map2k1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]

170911

Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]

171525

Polk; DNA polymerase kappa [KO:K03511] [EC:2.7.7.7]

24185

Akt1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]

24329

Egfr; epidermal growth factor receptor isoform 2 precursor [KO:K04361] [EC:2.7.10.1]

24337

Erbb2; receptor tyrosine-protein kinase erbB-2 precursor [KO:K05083] [EC:2.7.10.1]

24525

Kras; GTPase KRas [KO:K07827]

24703

Raf1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:2.7.11.1]

24708

Rb1; retinoblastoma-associated protein [KO:K06618]

24827

Tgfa; protransforming growth factor alpha preproprotein [KO:K08774]

24842

Tp53; cellular tumor antigen p53 [KO:K04451]

24887

Bax; apoptosis regulator BAX [KO:K02159]

24888

Bcl2l1; bcl-2-like protein 1 isoform 2 [KO:K04570]

25096

Pld1; phospholipase D1 isoform 2 [KO:K01115] [EC:3.1.4.4]

25097

Pld2; phospholipase D2 [KO:K01115] [EC:3.1.4.4]

25112

Gadd45a; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]

25124

Stat1; signal transducer and activator of transcription 1-alpha/beta isoform beta [KO:K11220]

25125

Stat3; signal transducer and activator of transcription 3 [KO:K04692]

25163

Cdkn2a; cyclin-dependent kinase inhibitor 2A [KO:K06621]

25233

Akt2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]

25272

Mapk10; mitogen-activated protein kinase 10 isoform 2 [KO:K04440] [EC:2.7.11.24]

25313

Egf; pro-epidermal growth factor precursor [KO:K04357]

25513

Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]

25631

Smad3; mothers against decapentaplegic homolog 3 [KO:K23605]

25717

Tgfb3; transforming growth factor beta-3 proprotein preproprotein [KO:K13377]

291005

Gadd45g; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]

291105

E2f3; transcription factor E2F3 [KO:K06620]

29357

Smad2; mothers against decapentaplegic homolog 2 [KO:K04500]

29414

Akt3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]

29591

Tgfbr1; TGF-beta receptor type-1 precursor [KO:K04674] [EC:2.7.11.30]

29622

Ralgds; ral guanine nucleotide dissociation stimulator isoform 1 [KO:K08732]

29741

Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]

299626

Gadd45b; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]

309165

Rela; transcription factor p65 [KO:K04735]

309295

Ikbkg; NF-kappa-B essential modulator [KO:K07210]

309361

Chuk; inhibitor of nuclear factor kappa-B kinase subunit alpha [KO:K04467] [EC:2.7.11.10]

360254

Brca2; breast cancer type 2 susceptibility protein homolog [KO:K08775]

361696

Rps6kb2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]

363509

Arhgef6; rho guanine nucleotide exchange factor 6 [KO:K05729]

363875

Rac1; ras-related C3 botulinum toxin substrate 1 [KO:K04392]

366508

Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]

366957

Rac2; ras-related C3 botulinum toxin substrate 2 [KO:K07860]

367149

Bax-ps1; apoptosis regulator BAX-like [KO:K02159]

399489

E2f1; transcription factor E2F1 [KO:K17454]

499870

Rad51; DNA repair protein RAD51 homolog 1 [KO:K04482]

50554

Smad4; mothers against decapentaplegic homolog 4 [KO:K04501]

50658

Mapk9; mitogen-activated protein kinase 9 isoform 2 [KO:K04440] [EC:2.7.11.24]

50689

Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]

56718

Mtor; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]

58918

Casp9; caspase-9 [KO:K04399] [EC:3.4.22.62]

58919

Ccnd1; G1/S-specific cyclin-D1 [KO:K04503]

59086

Tgfb1; transforming growth factor beta-1 proprotein precursor [KO:K13375]

60664

Pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]

64363

Araf; serine/threonine-protein kinase A-Raf isoform 1 [KO:K08845] [EC:2.7.11.1]

64465

Cdc42; cell division control protein 42 homolog [KO:K04393]

64639

Bad; bcl2-associated agonist of cell death [KO:K02158]

681314

[KO:K02159]

684111

E2f2; transcription factor E2F2 isoform X2 [KO:K09389]

688319

Rac3; ras-related C3 botulinum toxin substrate 3 [KO:K07861]

81736

Nfkb1; nuclear factor NF-kappa-B p105 subunit isoform 2 [KO:K02580]

81757

Rala; ras-related protein Ral-A [KO:K07834]

81809

Tgfb2; transforming growth factor beta-2 proprotein precursor [KO:K13376]

81810

Tgfbr2; TGF-beta receptor type-2 precursor [KO:K04388] [EC:2.7.11.30]

83785

Vegfa; vascular endothelial growth factor A isoform 6 precursor [KO:K05448]

83840

Rps6kb1; ribosomal protein S6 kinase beta-1 [KO:K04688] [EC:2.7.11.1]

84014

Ralbp1; ralA-binding protein 1 [KO:K08773]

84351

Ikbkb; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]

84598

Jak1; tyrosine-protein kinase JAK1 [KO:K11217] [EC:2.7.10.2]

85243

Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]

94201

Cdk4; cyclin-dependent kinase 4 isoform 1 [KO:K02089] [EC:2.7.11.22]

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

PMID:12459728

Authors

Bardeesy N, DePinho RA.

Title

Pancreatic cancer biology and genetics.

Journal

Nat Rev Cancer 2:897-909 (2002)
DOI:10.1038/nrc949

Reference

PMID:11407945

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

PMID:12946833

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

PMID:16702400

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

PMID:10740269

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

PMID:12648469

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

PMID:14967450

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

PMID:14586404

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

PMID:12545153

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

PMID:14580692

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

PMID:12079267

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

PMID:15774796