KEGG PATHWAY: ko05212

PATHWAY: ko05212

Entry

ko05212                     Pathway

Name

Pancreatic cancer

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

ko05212

Pancreatic cancer

Disease

H00019

Pancreatic cancer

Orthology

K00922

PIK3CA_B_D; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153]

K01115

PLD1_2; phospholipase D1/2 [EC:3.1.4.4]

K02089

CDK4; cyclin-dependent kinase 4 [EC:2.7.11.22]

K02091

CDK6; cyclin-dependent kinase 6 [EC:2.7.11.22]

K02158

BAD; Bcl-2-antagonist of cell death

K02159

BAX; apoptosis regulator BAX

K02580

NFKB1; nuclear factor NF-kappa-B p105 subunit

K02649

PIK3R1_2_3; phosphoinositide-3-kinase regulatory subunit alpha/beta/delta

K03511

POLK; DNA polymerase kappa [EC:2.7.7.7]

K04357

EGF; epidermal growth factor

K04361

EGFR, ERBB1; epidermal growth factor receptor [EC:2.7.10.1]

K04365

BRAF; B-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]

K04366

RAF1; RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]

K04368

MAP2K1, MEK1; mitogen-activated protein kinase kinase 1 [EC:2.7.12.2]

K04371

ERK, MAPK1_3; mitogen-activated protein kinase 1/3 [EC:2.7.11.24]

K04388

TGFBR2; TGF-beta receptor type-2 [EC:2.7.11.30]

K04392

RAC1; Ras-related C3 botulinum toxin substrate 1

K04393

CDC42; cell division control protein 42

K04399

CASP9; caspase 9 [EC:3.4.22.62]

K04402

GADD45; growth arrest and DNA-damage-inducible protein

K04440

JNK; mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24]

K04451

TP53, P53; tumor protein p53

K04456

AKT; RAC serine/threonine-protein kinase [EC:2.7.11.1]

K04467

IKBKA, IKKA, CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha [EC:2.7.11.10]

K04482

RAD51; DNA repair protein RAD51

K04500

SMAD2; mothers against decapentaplegic homolog 2

K04501

SMAD4; mothers against decapentaplegic homolog 4

K04503

CCND1; G1/S-specific cyclin-D1

K04570

BCL2L1, bcl-xL; Bcl-2-like 1 (apoptosis regulator Bcl-X)

K04674

TGFBR1, ALK5; TGF-beta receptor type-1 [EC:2.7.11.30]

K04688

RPS6KB; ribosomal protein S6 kinase beta [EC:2.7.11.1]

K04692

STAT3; signal transducer and activator of transcription 3

K04735

RELA; transcription factor p65

K05083

ERBB2, HER2, CD340; receptor tyrosine-protein kinase erbB-2 [EC:2.7.10.1]

K05448

VEGFA; vascular endothelial growth factor A

K05729

ARHGEF6, PIXA; Rho guanine nucleotide exchange factor 6

K06618

RB1; retinoblastoma-associated protein

K06620

E2F3; transcription factor E2F3

K06621

CDKN2A, P16, INK4A; cyclin-dependent kinase inhibitor 2A

K06625

CDKN1A, P21, CIP1; cyclin-dependent kinase inhibitor 1A

K07203

MTOR, FRAP, TOR; serine/threonine-protein kinase mTOR [EC:2.7.11.1]

K07209

IKBKB, IKKB; inhibitor of nuclear factor kappa-B kinase subunit beta [EC:2.7.11.10]

K07210

IKBKG, IKKG, NEMO; inhibitor of nuclear factor kappa-B kinase subunit gamma

K07827

KRAS, KRAS2; GTPase KRas

K07834

RALA; Ras-related protein Ral-A

K07835

RALB; Ras-related protein Ral-B

K07860

RAC2; Ras-related C3 botulinum toxin substrate 2

K07861

RAC3; Ras-related C3 botulinum toxin substrate 3

K08732

RALGDS; ral guanine nucleotide dissociation stimulator

K08773

RALBP1; RalA-binding protein 1

K08774

TGFA; transforming growth factor, alpha

K08775

BRCA2, FANCD1; breast cancer 2 susceptibility protein

K08845

ARAF, ARAF1; A-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]

K09389

E2F2; transcription factor E2F2

K10140

DDB2; DNA damage-binding protein 2

K11217

JAK1; Janus kinase 1 [EC:2.7.10.2]

K11220

STAT1; signal transducer and activator of transcription 1

K13375

TGFB1; transforming growth factor beta-1

K13376

TGFB2; transforming growth factor beta-2

K13377

TGFB3; transforming growth factor beta-3

K14021

BAK, BAK1; Bcl-2 homologous antagonist/killer

K17454

E2F1; transcription factor E2F1

K23605

SMAD3; mothers against decapentaplegic homolog 3

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