KEGG   PATHWAY: ko05205
ko05205                     Pathway                                

Proteoglycans in cancer
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.
Human Diseases; Cancer: overview
Pathway map
ko05205  Proteoglycans in cancer

K06256  CD44 antigen
K05704  tyrosine-protein kinase Src [EC:]
K06106  cortactin
K05083  receptor tyrosine-protein kinase erbB-2 [EC:]
K04364  growth factor receptor-bound protein 2
K05730  guanine nucleotide exchange factor VAV
K02833  GTPase HRas
K07827  GTPase KRas
K07828  GTPase NRas
K07829  Ras-related protein R-Ras
K07830  Ras-related protein R-Ras2
K07831  Ras-related protein M-Ras
K04365  B-Raf proto-oncogene serine/threonine-protein kinase [EC:]
K04366  RAF proto-oncogene serine/threonine-protein kinase [EC:]
K08845  A-Raf proto-oncogene serine/threonine-protein kinase [EC:]
K04368  mitogen-activated protein kinase kinase 1 [EC:]
K04369  mitogen-activated protein kinase kinase 2 [EC:]
K04371  mitogen-activated protein kinase 1/3 [EC:]
K04392  Ras-related C3 botulinum toxin substrate 1
K16848  Ras GTPase-activating-like protein IQGAP1
K04393  cell division control protein 42
K04375  ETS domain-containing protein Elk-1
K08550  estrogen receptor alpha
K04503  G1/S-specific cyclin-D1
K05692  actin beta/gamma 1
K04437  filamin
K04409  p21-activated kinase 1 [EC:]
K05731  T-lymphoma invasion and metastasis-inducing protein 1
K12330  Rho guanine nucleotide exchange factor 1
K04513  Ras homolog gene family, member A
K04514  Rho-associated protein kinase 1 [EC:]
K17388  Rho-associated protein kinase 2 [EC:]
K10380  ankyrin
K09593  GRB2-associated-binding protein 1
K00922  phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:]
K02649  phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K04456  RAC serine/threonine-protein kinase [EC:]
K05742  solute carrier family 9 (sodium/hydrogen exchanger), member 1
K06269  serine/threonine-protein phosphatase PP1 catalytic subunit [EC:]
K06270  protein phosphatase 1 regulatory subunit 12A
K12329  protein phosphatase 1 regulatory subunit 12B
K17457  protein phosphatase 1 regulatory subunit 12C
K07532  Rho guanine nucleotide exchange factor 12
K05860  phosphatidylinositol phospholipase C, epsilon [EC:]
K04958  inositol 1,4,5-triphosphate receptor type 1
K04959  inositol 1,4,5-triphosphate receptor type 2
K04960  inositol 1,4,5-triphosphate receptor type 3
K04515  calcium/calmodulin-dependent protein kinase (CaM kinase) II [EC:]
K10164  homeobox protein Nanog
K12823  ATP-dependent RNA helicase DDX5/DBP2 [EC:]
K03685  ribonuclease III [EC:]
K04692  signal transducer and activator of transcription 3
K16863  microRNA 21
K09069  twist
K16864  microRNA 10a
K17393  microRNA 10b
K09295  homrobox protein Hox-D10
K04660  decorin
K05459  insulin-like growth factor 1
K05087  insulin-like growth factor 1 receptor [EC:]
K07203  serine/threonine-protein kinase mTOR [EC:]
K06276  3-phosphoinositide dependent protein kinase-1 [EC:]
K04688  ribosomal protein S6 kinase beta [EC:]
K03258  translation initiation factor 4B
K02991  small subunit ribosomal protein S6e
K04361  epidermal growth factor receptor [EC:]
K06278  caveolin 1
K12958  caveolin 2
K12959  caveolin 3
K06497  CD63 antigen
K06625  cyclin-dependent kinase inhibitor 1A
K02187  caspase 3 [EC:]
K13375  transforming growth factor beta-1
K10159  toll-like receptor 2
K10160  toll-like receptor 4
K16865  programmed cell death protein 4
K03156  tumor necrosis factor superfamily, member 2
K05425  interleukin 12B
K05084  receptor tyrosine-protein kinase erbB-3 [EC:]
K05085  receptor tyrosine-protein kinase erbB-4 [EC:]
K04377  Myc proto-oncogene protein
K02105  catenin beta 1
K08268  hypoxia-inducible factor 1 alpha
K09108  transcription factor AP-4
K05448  vascular endothelial growth factor A
K05098  kinase insert domain protein receptor [EC:]
K05099  proto-oncogene tyrosine-protein kinase Met [EC:]
K04707  E3 ubiquitin-protein ligase CBL [EC:]
K16866  metalloproteinase inhibitor 3
K16857  thrombospondin 1
K01398  matrix metalloproteinase-2 (gelatinase A) [EC:]
K01403  matrix metalloproteinase-9 (gelatinase B) [EC:]
K08122  lumican
K04389  tumor necrosis factor ligand superfamily member 6
K04390  tumor necrosis factor receptor superfamily member 6
K06643  E3 ubiquitin-protein ligase Mdm2 [EC:]
K04451  tumor protein p53
K13376  transforming growth factor beta-2
K04500  mothers against decapentaplegic homolog 2
K07964  heparanase [EC:]
K07965  heparanase 2 [EC:3.2.1.-]
K06257  syndecan 1
K01348  urokinase plasminogen activator [EC:]
K03985  plasminogen activator, urokinase receptor
K06236  collagen type I alpha
K06481  integrin alpha 2
K05719  integrin beta 1
K06251  vitronectin
K06487  integrin alpha V
K06493  integrin beta 3
K05717  fibronectin 1
K06588  integrin beta 5
K05460  hepatocyte growth factor
K03209  wingless-type MMTV integration site family, member 1
K02432  frizzled 1/7
K02235  frizzled 2
K02329  frizzled 3
K02354  frizzled 4
K02375  frizzled 5/8
K02376  frizzled 6
K02842  frizzled 9/10
K06484  integrin alpha 5
K16336  syndecan 2
K08007  villin 2 (ezrin)
K05762  radixin
K05763  moesin
K16338  syndecan 4
K18497  fibroblast growth factor 2
K04362  fibroblast growth factor receptor 1 [EC:]
K12461  fibroblast growth factor receptor substrate 2
K07293  tyrosine-protein phosphatase non-receptor type 11 [EC:]
K03099  son of sevenless
K01116  phosphatidylinositol phospholipase C, gamma-1 [EC:]
K05859  phosphatidylinositol phospholipase C, gamma-2 [EC:]
K02677  classical protein kinase C alpha type [EC:]
K19662  classical protein kinase C beta type [EC:]
K19663  classical protein kinase C gamma type [EC:]
K16867  NUDT16-like protein 1
K05760  paxillin
K05725  focal adhesion kinase 1 [EC:]
K08523  heparin-binding EGF-like growth factor
K08107  glypican 1
K13769  insulin-like growth factor 2
K08109  glypican 3
K00182  wingless-type MMTV integration site family, member 2
K00312  wingless-type MMTV integration site family, member 3
K00408  wingless-type MMTV integration site family, member 4
K00444  wingless-type MMTV integration site family, member 5
K00445  wingless-type MMTV integration site family, member 6
K00572  wingless-type MMTV integration site family, member 7
K00714  wingless-type MMTV integration site family, member 8
K01064  wingless-type MMTV integration site family, member 9
K01357  wingless-type MMTV integration site family, member 10
K01384  wingless-type MMTV integration site family, member 11
K01558  wingless-type MMTV integration site family, member 16
K11988  sonic hedgehog
K11989  indian hedgehog
K06225  patched 1
K06226  smoothened
K06255  basement membrane-specific heparan sulfate proteoglycan core protein
K01365  cathepsin L [EC:]
K04345  protein kinase A [EC:]
K04441  p38 MAP kinase [EC:]
K09543  heat shock protein beta-2
K05697  tyrosine-protein phosphatase non-receptor type 6 [EC:]
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
Bourguignon LY
Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression.
Semin Cancer Biol 18:251-9 (2008)
Briggs MW, Sacks DB
IQGAP1 as signal integrator: Ca2+, calmodulin, Cdc42 and the cytoskeleton.
FEBS Lett 542:7-11 (2003)
Bourguignon LY, Singleton PA, Zhu H, Diedrich F
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.
J Biol Chem 278:29420-34 (2003)
Bourguignon LY, Gilad E, Rothman K, Peyrollier K
Hyaluronan-CD44 interaction with IQGAP1 promotes Cdc42 and ERK signaling, leading to actin binding, Elk-1/estrogen receptor transcriptional activation, and ovarian cancer progression.
J Biol Chem 280:11961-72 (2005)
Turley EA, Noble PW, Bourguignon LY
Signaling properties of hyaluronan receptors.
J Biol Chem 277:4589-92 (2002)
Bourguignon LY, Zhu H, Chu A, Iida N, Zhang L, Hung MC
Interaction between the adhesion receptor, CD44, and the oncogene product, p185HER2, promotes human ovarian tumor cell activation.
J Biol Chem 272:27913-8 (1997)
Neill T, Schaefer L, Iozzo RV
Decorin: a guardian from the matrix.
Am J Pathol 181:380-7 (2012)
Neill T, Painter H, Buraschi S, Owens RT, Lisanti MP, Schaefer L, Iozzo RV
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.
J Biol Chem 287:5492-506 (2012)
Goldoni S, Humphries A, Nystrom A, Sattar S, Owens RT, McQuillan DJ, Ireton K, Iozzo RV
Decorin is a novel antagonistic ligand of the Met receptor.
J Cell Biol 185:743-54 (2009)
Zhu JX, Goldoni S, Bix G, Owens RT, McQuillan DJ, Reed CC, Iozzo RV
Decorin evokes protracted internalization and degradation of the epidermal growth factor receptor via caveolar endocytosis.
J Biol Chem 280:32468-79 (2005)
Buraschi S, Pal N, Tyler-Rubinstein N, Owens RT, Neill T, Iozzo RV
Decorin antagonizes Met receptor activity and down-regulates {beta}-catenin and Myc levels.
J Biol Chem 285:42075-85 (2010)
Goldoni S, Iozzo RV
Tumor microenvironment: Modulation by decorin and related molecules harboring leucine-rich tandem motifs.
Int J Cancer 123:2473-9 (2008)
Sofeu Feugaing DD, Gotte M, Viola M
More than matrix: the multifaceted role of decorin in cancer.
Eur J Cell Biol 92:1-11 (2013)
Merline R, Moreth K, Beckmann J, Nastase MV, Zeng-Brouwers J, Tralhao JG, Lemarchand P, Pfeilschifter J, Schaefer RM, Iozzo RV, Schaefer L
Signaling by the matrix proteoglycan decorin controls inflammation and cancer through PDCD4 and MicroRNA-21.
Sci Signal 4:ra75 (2011)
Teng YH, Aquino RS, Park PW
Molecular functions of syndecan-1 in disease.
Matrix Biol 31:3-16 (2012)
Derksen PW, Keehnen RM, Evers LM, van Oers MH, Spaargaren M, Pals ST
Cell surface proteoglycan syndecan-1 mediates hepatocyte growth factor binding and promotes Met signaling in multiple myeloma.
Blood 99:1405-10 (2002)
Fux L, Ilan N, Sanderson RD, Vlodavsky I
Heparanase: busy at the cell surface.
Trends Biochem Sci 34:511-9 (2009)
Purushothaman A, Chen L, Yang Y, Sanderson RD
Heparanase stimulation of protease expression implicates it as a master regulator of the aggressive tumor phenotype in myeloma.
J Biol Chem 283:32628-36 (2008)
Beauvais DM, Ell BJ, McWhorter AR, Rapraeger AC
Syndecan-1 regulates alphavbeta3 and alphavbeta5 integrin activation during angiogenesis and is blocked by synstatin, a novel peptide inhibitor.
J Exp Med 206:691-705 (2009)
Mahtouk K, Tjin EP, Spaargaren M, Pals ST
The HGF/MET pathway as target for the treatment of multiple myeloma and B-cell lymphomas.
Biochim Biophys Acta 1806:208-19 (2010)
Munesue S, Kusano Y, Oguri K, Itano N, Yoshitomi Y, Nakanishi H, Yamashina I, Okayama M
The role of syndecan-2 in regulation of actin-cytoskeletal organization of Lewis lung carcinoma-derived metastatic clones.
Biochem J 363:201-9 (2002)
Nugent MA, Iozzo RV
Fibroblast growth factor-2.
Int J Biochem Cell Biol 32:115-20 (2000)
Baciu PC, Saoncella S, Lee SH, Denhez F, Leuthardt D, Goetinck PF
Syndesmos, a protein that interacts with the cytoplasmic domain of syndecan-4, mediates cell spreading and actin cytoskeletal organization.
J Cell Sci 113 Pt 2:315-24 (2000)
Thodeti CK, Albrechtsen R, Grauslund M, Asmar M, Larsson C, Takada Y, Mercurio AM, Couchman JR, Wewer UM
ADAM12/syndecan-4 signaling promotes beta 1 integrin-dependent cell spreading through protein kinase Calpha and RhoA.
J Biol Chem 278:9576-84 (2003)
Beauvais DM, Rapraeger AC
Syndecans in tumor cell adhesion and signaling.
Reprod Biol Endocrinol 2:3 (2004)
Morgan MR, Humphries MJ, Bass MD
Synergistic control of cell adhesion by integrins and syndecans.
Nat Rev Mol Cell Biol 8:957-69 (2007)
Filmus J, Capurro M, Rast J
Genome Biol 9:224 (2008)
Filmus J, Capurro M
Glypican-3: a marker and a therapeutic target in hepatocellular carcinoma.
FEBS J 280:2471-6 (2013)
Gao W, Ho M
The role of glypican-3 in regulating Wnt in hepatocellular carcinomas.
Cancer Rep 1:14-19 (2011)
Filmus J, Capurro M
The role of glypicans in Hedgehog signaling.
Matrix Biol 35:248-52 (2014)
Cheng W, Tseng CJ, Lin TT, Cheng I, Pan HW, Hsu HC, Lee YM
Glypican-3-mediated oncogenesis involves the Insulin-like growth factor-signaling pathway.
Carcinogenesis 29:1319-26 (2008)
Iozzo RV, Sanderson RD
Proteoglycans in cancer biology, tumour microenvironment and angiogenesis.
J Cell Mol Med 15:1013-31 (2011)
Nikitovic D, Katonis P, Tsatsakis A, Karamanos NK, Tzanakakis GN
Lumican, a small leucine-rich proteoglycan.
IUBMB Life 60:818-23 (2008)
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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