KEGG   PATHWAY: ko05205
Entry
ko05205                     Pathway                                
Name
Proteoglycans in cancer
Description
Many proteoglycans (PGs) in the tumor microenvironment have been shown to be key macromolecules that contribute to biology of various types of cancer including proliferation, adhesion, angiogenesis and metastasis, affecting tumor progress. The four main types of proteoglycans include hyaluronan (HA), which does not occur as a PG but in free form, heparan sulfate proteoglycans (HSPGs), chondroitin sulfate proteoglycans (CSPGs), dematan sulfate proteoglycans (DSPG) and keratan sulfate proteoglycans (KSPGs) [BR:00535]. Among these proteoglycans such as HA, acting with CD44, promotes tumor cell growth and migration, whereas other proteoglycans such as syndecans (-1~-4), glypican (-1, -3) and perlecan may interact with growth factors, cytokines, morphogens and enzymes through HS chains [BR:00536], also leading to tumor growth and invasion. In contrast, some of the small leucine-rich proteolgycans, such as decorin and lumican, can function as tumor repressors, and modulate the signaling pathways by the interaction of their core proteins and multiple receptors.
Class
Human Diseases; Cancer: overview
Pathway map
ko05205  Proteoglycans in cancer
ko05205

Orthology
K00182  WNT2; wingless-type MMTV integration site family, member 2
K00312  WNT3; wingless-type MMTV integration site family, member 3
K00408  WNT4; wingless-type MMTV integration site family, member 4
K00444  WNT5; wingless-type MMTV integration site family, member 5
K00445  WNT6; wingless-type MMTV integration site family, member 6
K00572  WNT7; wingless-type MMTV integration site family, member 7
K00714  WNT8; wingless-type MMTV integration site family, member 8
K00922  PIK3CA_B_D; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153]
K01064  WNT9; wingless-type MMTV integration site family, member 9
K01116  PLCG1; phosphatidylinositol phospholipase C, gamma-1 [EC:3.1.4.11]
K01348  PLAU; urokinase plasminogen activator [EC:3.4.21.73]
K01357  WNT10; wingless-type MMTV integration site family, member 10
K01365  CTSL; cathepsin L [EC:3.4.22.15]
K01384  WNT11; wingless-type MMTV integration site family, member 11
K01398  MMP2; matrix metalloproteinase-2 (gelatinase A) [EC:3.4.24.24]
K01403  MMP9; matrix metalloproteinase-9 (gelatinase B) [EC:3.4.24.35]
K01558  WNT16; wingless-type MMTV integration site family, member 16
K02105  CTNNB1; catenin beta 1
K02187  CASP3; caspase 3 [EC:3.4.22.56]
K02235  FZD2; frizzled 2
K02329  FZD3; frizzled 3
K02354  FZD4, fz4, CD344; frizzled 4
K02375  FZD5_8, fz2; frizzled 5/8
K02376  FZD6; frizzled 6
K02432  FZD1_7, fz; frizzled 1/7
K02649  PIK3R1_2_3; phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K02677  PRKCA; classical protein kinase C alpha type [EC:2.7.11.13]
K02833  HRAS; GTPase HRas
K02842  FZD9_10, CD349_50; frizzled 9/10
K02991  RP-S6e, RPS6; small subunit ribosomal protein S6e
K03099  SOS; son of sevenless
K03156  TNF, TNFA; tumor necrosis factor superfamily, member 2
K03209  WNT1; wingless-type MMTV integration site family, member 1
K03258  EIF4B; translation initiation factor 4B
K03685  rnc, DROSHA, RNT1; ribonuclease III [EC:3.1.26.3]
K03985  PLAUR, CD87; plasminogen activator, urokinase receptor
K04345  PKA; protein kinase A [EC:2.7.11.11]
K04361  EGFR, ERBB1; epidermal growth factor receptor [EC:2.7.10.1]
K04362  FGFR1, CD331; fibroblast growth factor receptor 1 [EC:2.7.10.1]
K04364  GRB2; growth factor receptor-bound protein 2
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]
K04369  MAP2K2, MEK2; mitogen-activated protein kinase kinase 2 [EC:2.7.12.2]
K04371  ERK, MAPK1_3; mitogen-activated protein kinase 1/3 [EC:2.7.11.24]
K04375  ELK1; ETS domain-containing protein Elk-1
K04377  MYC; Myc proto-oncogene protein
K04389  TNFSF6, FASL, CD178; tumor necrosis factor ligand superfamily member 6
K04390  TNFRSF6, FAS, CD95; tumor necrosis factor receptor superfamily member 6
K04392  RAC1; Ras-related C3 botulinum toxin substrate 1
K04393  CDC42; cell division control protein 42
K04409  PAK1; p21-activated kinase 1 [EC:2.7.11.1]
K04437  FLNA; filamin-A
K04441  P38; p38 MAP kinase [EC:2.7.11.24]
K04451  TP53, P53; tumor protein p53
K04456  AKT; RAC serine/threonine-protein kinase [EC:2.7.11.1]
K04500  SMAD2; mothers against decapentaplegic homolog 2
K04503  CCND1; G1/S-specific cyclin-D1
K04513  RHOA; Ras homolog gene family, member A
K04514  ROCK1; Rho-associated protein kinase 1 [EC:2.7.11.39]
K04515  CAMK2; calcium/calmodulin-dependent protein kinase (CaM kinase) II [EC:2.7.11.17]
K04660  DCN; decorin
K04688  RPS6KB; ribosomal protein S6 kinase beta [EC:2.7.11.1]
K04692  STAT3; signal transducer and activator of transcription 3
K04707  CBL; E3 ubiquitin-protein ligase CBL [EC:2.3.2.27]
K04958  ITPR1; inositol 1,4,5-triphosphate receptor type 1
K04959  ITPR2; inositol 1,4,5-triphosphate receptor type 2
K04960  ITPR3; inositol 1,4,5-triphosphate receptor type 3
K05083  ERBB2, HER2, CD340; receptor tyrosine-protein kinase erbB-2 [EC:2.7.10.1]
K05084  ERBB3, HER3; receptor tyrosine-protein kinase erbB-3 [EC:2.7.10.1]
K05085  ERBB4, HER4; receptor tyrosine-protein kinase erbB-4 [EC:2.7.10.1]
K05087  IGF1R, CD221; insulin-like growth factor 1 receptor [EC:2.7.10.1]
K05098  KDR, VEGFR2, CD309; kinase insert domain protein receptor [EC:2.7.10.1]
K05099  MET, HGFR; proto-oncogene tyrosine-protein kinase Met [EC:2.7.10.1]
K05425  IL12B; interleukin 12B
K05448  VEGFA; vascular endothelial growth factor A
K05459  IGF1; insulin-like growth factor 1
K05460  HGF; hepatocyte growth factor
K05692  ACTB_G1; actin beta/gamma 1
K05697  PTPN6, SHP1; tyrosine-protein phosphatase non-receptor type 6 [EC:3.1.3.48]
K05704  SRC; tyrosine-protein kinase Src [EC:2.7.10.2]
K05717  FN1; fibronectin 1
K05719  ITGB1, CD29; integrin beta 1
K05725  PTK2, FAK; focal adhesion kinase 1 [EC:2.7.10.2]
K05730  VAV; guanine nucleotide exchange factor VAV
K05731  TIAM1; T-lymphoma invasion and metastasis-inducing protein 1
K05742  SLC9A1, NHE1; solute carrier family 9 (sodium/hydrogen exchanger), member 1
K05760  PXN; paxillin
K05762  RDX; radixin
K05763  MSN; moesin
K05859  PLCG2; phosphatidylinositol phospholipase C, gamma-2 [EC:3.1.4.11]
K05860  PLCE; phosphatidylinositol phospholipase C, epsilon [EC:3.1.4.11]
K06106  CTTN, EMS1; cortactin
K06225  PTCH1; patched 1
K06226  SMO; smoothened
K06236  COL1A; collagen type I alpha
K06251  VTN; vitronectin
K06255  HSPG2; basement membrane-specific heparan sulfate proteoglycan core protein
K06256  CD44; CD44 antigen
K06257  SDC1, CD138; syndecan 1
K06269  PPP1C; serine/threonine-protein phosphatase PP1 catalytic subunit [EC:3.1.3.16]
K06270  PPP1R12A, MYPT1; protein phosphatase 1 regulatory subunit 12A
K06276  PDPK1; 3-phosphoinositide dependent protein kinase-1 [EC:2.7.11.1]
K06278  CAV1; caveolin 1
K06481  ITGA2, CD49b; integrin alpha 2
K06484  ITGA5, CD49e; integrin alpha 5
K06487  ITGAV, CD51; integrin alpha V
K06493  ITGB3, CD61; integrin beta 3
K06497  CD63, MLA1, TSPAN30; CD63 antigen
K06588  ITGB5; integrin beta 5
K06625  CDKN1A, P21, CIP1; cyclin-dependent kinase inhibitor 1A
K06643  MDM2; E3 ubiquitin-protein ligase Mdm2 [EC:2.3.2.27]
K07203  MTOR, FRAP, TOR; serine/threonine-protein kinase mTOR [EC:2.7.11.1]
K07293  PTPN11, SHP2; tyrosine-protein phosphatase non-receptor type 11 [EC:3.1.3.48]
K07532  ARHGEF12, LARG; Rho guanine nucleotide exchange factor 12
K07827  KRAS, KRAS2; GTPase KRas
K07828  NRAS; GTPase NRas
K07829  RRAS; Ras-related protein R-Ras
K07830  RRAS2, TC21; Ras-related protein R-Ras2
K07831  MRAS; Ras-related protein M-Ras
K07964  HPSE; heparanase [EC:3.2.1.166]
K07965  HPSE2; heparanase 2 [EC:3.2.1.-]
K08007  EZR, VIL2; ezrin
K08107  GPC1; glypican 1
K08109  GPC3; glypican 3
K08122  LUM; lumican
K08268  HIF1A; hypoxia-inducible factor 1 alpha
K08523  HBEGF; heparin-binding EGF-like growth factor
K08550  ESR1, NR3A1; estrogen receptor alpha
K08845  ARAF, ARAF1; A-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K09069  TWIST; twist
K09108  TFAP4; transcription factor AP-4
K09255  ANK2, ANKB; ankyrin-2
K09259  ANK3, ANKG; ankyrin-3
K09295  HOXD10; homrobox protein Hox-D10
K09543  HSPB2; heat shock protein beta-2
K09593  GAB1; GRB2-associated-binding protein 1
K10159  TLR2, CD282; toll-like receptor 2
K10160  TLR4, CD284; toll-like receptor 4
K10164  NANOG; homeobox protein Nanog
K10380  ANK1; ankyrin-1
K11988  SHH; sonic hedgehog
K11989  IHH; indian hedgehog
K12329  PPP1R12B, MYPT2; protein phosphatase 1 regulatory subunit 12B
K12330  ARHGEF1; Rho guanine nucleotide exchange factor 1
K12461  FRS2; fibroblast growth factor receptor substrate 2
K12823  DDX5, DBP2; ATP-dependent RNA helicase DDX5/DBP2 [EC:5.6.2.7]
K12958  CAV2; caveolin 2
K12959  CAV3; caveolin 3
K13375  TGFB1; transforming growth factor beta-1
K13376  TGFB2; transforming growth factor beta-2
K13769  IGF2; insulin-like growth factor 2
K16336  SDC2, CD362; syndecan 2
K16338  SDC4; syndecan 4
K16848  IQGAP1; Ras GTPase-activating-like protein IQGAP1
K16857  THBS1; thrombospondin 1
K16863  MIR21; microRNA 21
K16864  MIR10A; microRNA 10a
K16865  PDCD4; programmed cell death protein 4
K16866  TIMP3; metalloproteinase inhibitor 3
K16867  NUDT16L1, SDOS; NUDT16-like protein 1
K17388  ROCK2; Rho-associated protein kinase 2 [EC:2.7.11.39]
K17393  MIR10B; microRNA 10b
K17457  PPP1R12C, MBS85; protein phosphatase 1 regulatory subunit 12C
K18497  FGF2; fibroblast growth factor 2
K19662  PRKCB; classical protein kinase C beta type [EC:2.7.11.13]
K19663  PRKCG; classical protein kinase C gamma type [EC:2.7.11.13]
Compound
C00426  Dermatan sulfate
C00573  Keratan sulfate
C00607  Chondroitin sulfate
C00925  Heparan sulfate
G10505  Hyaluronic acid
G13063  Binding domain for FGF2 in heparin/heparan sulfate
G13064  Binding domain for HGF in heparin/heparan sulfate
Reference
PMID:18450475
  Authors
Bourguignon LY
  Title
Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression.
  Journal
Semin Cancer Biol 18:251-9 (2008)
DOI:10.1016/j.semcancer.2008.03.007
Reference
PMID:12729888
  Authors
Briggs MW, Sacks DB
  Title
IQGAP1 as signal integrator: Ca2+, calmodulin, Cdc42 and the cytoskeleton.
  Journal
FEBS Lett 542:7-11 (2003)
DOI:10.1016/S0014-5793(03)00333-8
Reference
PMID:12748184
  Authors
Bourguignon LY, Singleton PA, Zhu H, Diedrich F
  Title
Hyaluronan-mediated CD44 interaction with RhoGEF and Rho kinase promotes Grb2-associated binder-1 phosphorylation and phosphatidylinositol 3-kinase signaling leading to cytokine (macrophage-colony stimulating factor) production and breast tumor progression.
  Journal
J Biol Chem 278:29420-34 (2003)
DOI:10.1074/jbc.M301885200
Reference
PMID:15655247
  Authors
Bourguignon LY, Gilad E, Rothman K, Peyrollier K
  Title
Hyaluronan-CD44 interaction with IQGAP1 promotes Cdc42 and ERK signaling, leading to actin binding, Elk-1/estrogen receptor transcriptional activation, and ovarian cancer progression.
  Journal
J Biol Chem 280:11961-72 (2005)
DOI:10.1074/jbc.M411985200
Reference
PMID:11717317
  Authors
Turley EA, Noble PW, Bourguignon LY
  Title
Signaling properties of hyaluronan receptors.
  Journal
J Biol Chem 277:4589-92 (2002)
DOI:10.1074/jbc.R100038200
Reference
PMID:9346940
  Authors
Bourguignon LY, Zhu H, Chu A, Iida N, Zhang L, Hung MC
  Title
Interaction between the adhesion receptor, CD44, and the oncogene product, p185HER2, promotes human ovarian tumor cell activation.
  Journal
J Biol Chem 272:27913-8 (1997)
DOI:10.1074/jbc.272.44.27913
Reference
PMID:22735579
  Authors
Neill T, Schaefer L, Iozzo RV
  Title
Decorin: a guardian from the matrix.
  Journal
Am J Pathol 181:380-7 (2012)
DOI:10.1016/j.ajpath.2012.04.029
Reference
PMID:22194599
  Authors
Neill T, Painter H, Buraschi S, Owens RT, Lisanti MP, Schaefer L, Iozzo RV
  Title
Decorin antagonizes the angiogenic network: concurrent inhibition of Met, hypoxia inducible factor 1alpha, vascular endothelial growth factor A, and induction of thrombospondin-1 and TIMP3.
  Journal
J Biol Chem 287:5492-506 (2012)
DOI:10.1074/jbc.M111.283499
Reference
PMID:19433454
  Authors
Goldoni S, Humphries A, Nystrom A, Sattar S, Owens RT, McQuillan DJ, Ireton K, Iozzo RV
  Title
Decorin is a novel antagonistic ligand of the Met receptor.
  Journal
J Cell Biol 185:743-54 (2009)
DOI:10.1083/jcb.200901129
Reference
PMID:15994311
  Authors
Zhu JX, Goldoni S, Bix G, Owens RT, McQuillan DJ, Reed CC, Iozzo RV
  Title
Decorin evokes protracted internalization and degradation of the epidermal growth factor receptor via caveolar endocytosis.
  Journal
J Biol Chem 280:32468-79 (2005)
DOI:10.1074/jbc.M503833200
Reference
PMID:20974860
  Authors
Buraschi S, Pal N, Tyler-Rubinstein N, Owens RT, Neill T, Iozzo RV
  Title
Decorin antagonizes Met receptor activity and down-regulates {beta}-catenin and Myc levels.
  Journal
J Biol Chem 285:42075-85 (2010)
DOI:10.1074/jbc.M110.172841
Reference
PMID:18798267
  Authors
Goldoni S, Iozzo RV
  Title
Tumor microenvironment: Modulation by decorin and related molecules harboring leucine-rich tandem motifs.
  Journal
Int J Cancer 123:2473-9 (2008)
DOI:10.1002/ijc.23930
Reference
PMID:23058688
  Authors
Sofeu Feugaing DD, Gotte M, Viola M
  Title
More than matrix: the multifaceted role of decorin in cancer.
  Journal
Eur J Cell Biol 92:1-11 (2013)
DOI:10.1016/j.ejcb.2012.08.004
Reference
PMID:22087031
  Authors
Merline R, Moreth K, Beckmann J, Nastase MV, Zeng-Brouwers J, Tralhao JG, Lemarchand P, Pfeilschifter J, Schaefer RM, Iozzo RV, Schaefer L
  Title
Signaling by the matrix proteoglycan decorin controls inflammation and cancer through PDCD4 and MicroRNA-21.
  Journal
Sci Signal 4:ra75 (2011)
DOI:10.1126/scisignal.2001868
Reference
PMID:22033227
  Authors
Teng YH, Aquino RS, Park PW
  Title
Molecular functions of syndecan-1 in disease.
  Journal
Matrix Biol 31:3-16 (2012)
DOI:10.1016/j.matbio.2011.10.001
Reference
PMID:11830493
  Authors
Derksen PW, Keehnen RM, Evers LM, van Oers MH, Spaargaren M, Pals ST
  Title
Cell surface proteoglycan syndecan-1 mediates hepatocyte growth factor binding and promotes Met signaling in multiple myeloma.
  Journal
Blood 99:1405-10 (2002)
DOI:10.1182/blood.V99.4.1405
Reference
PMID:19733083
  Authors
Fux L, Ilan N, Sanderson RD, Vlodavsky I
  Title
Heparanase: busy at the cell surface.
  Journal
Trends Biochem Sci 34:511-9 (2009)
DOI:10.1016/j.tibs.2009.06.005
Reference
PMID:18812315
  Authors
Purushothaman A, Chen L, Yang Y, Sanderson RD
  Title
Heparanase stimulation of protease expression implicates it as a master regulator of the aggressive tumor phenotype in myeloma.
  Journal
J Biol Chem 283:32628-36 (2008)
DOI:10.1074/jbc.M806266200
Reference
PMID:19255147
  Authors
Beauvais DM, Ell BJ, McWhorter AR, Rapraeger AC
  Title
Syndecan-1 regulates alphavbeta3 and alphavbeta5 integrin activation during angiogenesis and is blocked by synstatin, a novel peptide inhibitor.
  Journal
J Exp Med 206:691-705 (2009)
DOI:10.1084/jem.20081278
Reference
PMID:20655987
  Authors
Mahtouk K, Tjin EP, Spaargaren M, Pals ST
  Title
The HGF/MET pathway as target for the treatment of multiple myeloma and B-cell lymphomas.
  Journal
Biochim Biophys Acta 1806:208-19 (2010)
DOI:10.1016/j.bbcan.2010.07.006
Reference
PMID:11931647
  Authors
Munesue S, Kusano Y, Oguri K, Itano N, Yoshitomi Y, Nakanishi H, Yamashina I, Okayama M
  Title
The role of syndecan-2 in regulation of actin-cytoskeletal organization of Lewis lung carcinoma-derived metastatic clones.
  Journal
Biochem J 363:201-9 (2002)
DOI:10.1042/bj3630201
Reference
PMID:10687947
  Authors
Nugent MA, Iozzo RV
  Title
Fibroblast growth factor-2.
  Journal
Int J Biochem Cell Biol 32:115-20 (2000)
DOI:10.1016/S1357-2725(99)00123-5
Reference
PMID:10633082
  Authors
Baciu PC, Saoncella S, Lee SH, Denhez F, Leuthardt D, Goetinck PF
  Title
Syndesmos, a protein that interacts with the cytoplasmic domain of syndecan-4, mediates cell spreading and actin cytoskeletal organization.
  Journal
J Cell Sci 113 Pt 2:315-24 (2000)
Reference
PMID:12509413
  Authors
Thodeti CK, Albrechtsen R, Grauslund M, Asmar M, Larsson C, Takada Y, Mercurio AM, Couchman JR, Wewer UM
  Title
ADAM12/syndecan-4 signaling promotes beta 1 integrin-dependent cell spreading through protein kinase Calpha and RhoA.
  Journal
J Biol Chem 278:9576-84 (2003)
DOI:10.1074/jbc.M208937200
Reference
PMID:14711376
  Authors
Beauvais DM, Rapraeger AC
  Title
Syndecans in tumor cell adhesion and signaling.
  Journal
Reprod Biol Endocrinol 2:3 (2004)
DOI:10.1186/1477-7827-2-3
Reference
PMID:17971838
  Authors
Morgan MR, Humphries MJ, Bass MD
  Title
Synergistic control of cell adhesion by integrins and syndecans.
  Journal
Nat Rev Mol Cell Biol 8:957-69 (2007)
DOI:10.1038/nrm2289
Reference
PMID:18505598
  Authors
Filmus J, Capurro M, Rast J
  Title
Glypicans.
  Journal
Genome Biol 9:224 (2008)
DOI:10.1186/gb-2008-9-5-224
Reference
PMID:23305321
  Authors
Filmus J, Capurro M
  Title
Glypican-3: a marker and a therapeutic target in hepatocellular carcinoma.
  Journal
FEBS J 280:2471-6 (2013)
DOI:10.1111/febs.12126
Reference
PMID:22563565
  Authors
Gao W, Ho M
  Title
The role of glypican-3 in regulating Wnt in hepatocellular carcinomas.
  Journal
Cancer Rep 1:14-19 (2011)
Reference
PMID:24412155
  Authors
Filmus J, Capurro M
  Title
The role of glypicans in Hedgehog signaling.
  Journal
Matrix Biol 35:248-52 (2014)
DOI:10.1016/j.matbio.2013.12.007
Reference
PMID:18413366
  Authors
Cheng W, Tseng CJ, Lin TT, Cheng I, Pan HW, Hsu HC, Lee YM
  Title
Glypican-3-mediated oncogenesis involves the Insulin-like growth factor-signaling pathway.
  Journal
Carcinogenesis 29:1319-26 (2008)
DOI:10.1093/carcin/bgn091
Reference
PMID:21155971
  Authors
Iozzo RV, Sanderson RD
  Title
Proteoglycans in cancer biology, tumour microenvironment and angiogenesis.
  Journal
J Cell Mol Med 15:1013-31 (2011)
DOI:10.1111/j.1582-4934.2010.01236.x
Reference
PMID:18949819
  Authors
Nikitovic D, Katonis P, Tsatsakis A, Karamanos NK, Tzanakakis GN
  Title
Lumican, a small leucine-rich proteoglycan.
  Journal
IUBMB Life 60:818-23 (2008)
DOI:10.1002/iub.131
Related
pathway
ko04010  MAPK signaling pathway
ko04020  Calcium signaling pathway
ko04066  HIF-1 signaling pathway
ko04150  mTOR signaling pathway
ko04151  PI3K-Akt signaling pathway
ko04210  Apoptosis
ko04310  Wnt signaling pathway
ko04340  Hedgehog signaling pathway
ko04350  TGF-beta signaling pathway
ko04370  VEGF signaling pathway
ko04510  Focal adhesion
ko04520  Adherens junction
ko04810  Regulation of actin cytoskeleton

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