Entry
Name
Proteoglycans in cancer - Homo sapiens (human)
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
BRITE hierarchy
Pathway map
Ortholog table
Drug
D10382 Afuresertib hydrochloride (USAN)
D11239 Lumretuzumab (USAN/INN)
D11611 Infigratinib phosphate (USAN)
D11765 Necuparanib sodium (USAN)
Organism
Homo sapiens (human) [GN:
hsa ]
Gene
960 CD44; CD44 molecule (Indian blood group) [KO:K06256 ]
3059 HCLS1; hematopoietic cell-specific Lyn substrate 1 [KO:K06106 ]
2885 GRB2; growth factor receptor bound protein 2 [KO:K04364 ]
10451 VAV3; vav guanine nucleotide exchange factor 3 [KO:K05730 ]
7409 VAV1; vav guanine nucleotide exchange factor 1 [KO:K05730 ]
7410 VAV2; vav guanine nucleotide exchange factor 2 [KO:K05730 ]
3265 HRAS; HRas proto-oncogene, GTPase [KO:K02833 ]
3845 KRAS; KRAS proto-oncogene, GTPase [KO:K07827 ]
4893 NRAS; NRAS proto-oncogene, GTPase [KO:K07828 ]
8826 IQGAP1; IQ motif containing GTPase activating protein 1 [KO:K16848 ]
998 CDC42; cell division cycle 42 [KO:K04393 ]
2002 ELK1; ETS transcription factor ELK1 [KO:K04375 ]
7074 TIAM1; TIAM Rac1 associated GEF 1 [KO:K05731 ]
9138 ARHGEF1; Rho guanine nucleotide exchange factor 1 [KO:K12330 ]
387 RHOA; ras homolog family member A [KO:K04513 ]
6093 ROCK1; Rho associated coiled-coil containing protein kinase 1 [KO:K04514 ] [EC:2.7.11.1 ]
9475 ROCK2; Rho associated coiled-coil containing protein kinase 2 [KO:K17388 ] [EC:2.7.11.1 ]
2549 GAB1; GRB2 associated binding protein 1 [KO:K09593 ]
5290 PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922 ] [EC:2.7.1.153 ]
5293 PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922 ] [EC:2.7.1.153 ]
5291 PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922 ] [EC:2.7.1.153 ]
5295 PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649 ]
5296 PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649 ]
8503 PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649 ]
6548 SLC9A1; solute carrier family 9 member A1 [KO:K05742 ]
4659 PPP1R12A; protein phosphatase 1 regulatory subunit 12A [KO:K06270 ]
4660 PPP1R12B; protein phosphatase 1 regulatory subunit 12B [KO:K12329 ]
54776 PPP1R12C; protein phosphatase 1 regulatory subunit 12C [KO:K17457 ]
23365 ARHGEF12; Rho guanine nucleotide exchange factor 12 [KO:K07532 ]
3708 ITPR1; inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958 ]
3709 ITPR2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959 ]
3710 ITPR3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960 ]
815 CAMK2A; calcium/calmodulin dependent protein kinase II alpha [KO:K04515 ] [EC:2.7.11.17 ]
817 CAMK2D; calcium/calmodulin dependent protein kinase II delta [KO:K04515 ] [EC:2.7.11.17 ]
816 CAMK2B; calcium/calmodulin dependent protein kinase II beta [KO:K04515 ] [EC:2.7.11.17 ]
818 CAMK2G; calcium/calmodulin dependent protein kinase II gamma [KO:K04515 ] [EC:2.7.11.17 ]
6774 STAT3; signal transducer and activator of transcription 3 [KO:K04692 ]
7291 TWIST1; twist family bHLH transcription factor 1 [KO:K09069 ]
117581 TWIST2; twist family bHLH transcription factor 2 [KO:K09069 ]
3479 IGF1; insulin like growth factor 1 [KO:K05459 ]
1975 EIF4B; eukaryotic translation initiation factor 4B [KO:K03258 ]
1026 CDKN1A; cyclin dependent kinase inhibitor 1A [KO:K06625 ]
7040 TGFB1; transforming growth factor beta 1 [KO:K13375 ]
4609 MYC; MYC proto-oncogene, bHLH transcription factor [KO:K04377 ]
3091 HIF1A; hypoxia inducible factor 1 subunit alpha [KO:K08268 ]
7422 VEGFA; vascular endothelial growth factor A [KO:K05448 ]
7078 TIMP3; TIMP metallopeptidase inhibitor 3 [KO:K16866 ]
355 FAS; Fas cell surface death receptor [KO:K04390 ]
7042 TGFB2; transforming growth factor beta 2 [KO:K13376 ]
60495 HPSE2; heparanase 2 (inactive) [KO:K07965 ] [EC:3.2.1.-]
5329 PLAUR; plasminogen activator, urokinase receptor [KO:K03985 ]
1277 COL1A1; collagen type I alpha 1 chain [KO:K06236 ]
1278 COL1A2; collagen type I alpha 2 chain [KO:K06236 ]
10818 FRS2; fibroblast growth factor receptor substrate 2 [KO:K12461 ]
6654 SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099 ]
6655 SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099 ]
1839 HBEGF; heparin binding EGF like growth factor [KO:K08523 ]
3481 IGF2; insulin like growth factor 2 [KO:K13769 ]
6469 SHH; sonic hedgehog signaling molecule [KO:K11988 ]
3549 IHH; Indian hedgehog signaling molecule [KO:K11989 ]
6608 SMO; smoothened, frizzled class receptor [KO:K06226 ]
3339 HSPG2; heparan sulfate proteoglycan 2 [KO:K06255 ]
3316 HSPB2; heat shock protein family B (small) member 2 [KO:K09543 ]
Compound
G13063 Binding domain for FGF2 in heparin/heparan sulfate
G13064 Binding domain for HGF in heparin/heparan sulfate
Reference
Authors
Bourguignon LY
Title
Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression.
Journal
Reference
Authors
Briggs MW, Sacks DB
Title
IQGAP1 as signal integrator: Ca2+, calmodulin, Cdc42 and the cytoskeleton.
Journal
Reference
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
Reference
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
Reference
Authors
Turley EA, Noble PW, Bourguignon LY
Title
Signaling properties of hyaluronan receptors.
Journal
Reference
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
Reference
Authors
Neill T, Schaefer L, Iozzo RV
Title
Decorin: a guardian from the matrix.
Journal
Reference
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
Reference
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
Reference
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
Reference
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
Reference
Authors
Goldoni S, Iozzo RV
Title
Tumor microenvironment: Modulation by decorin and related molecules harboring leucine-rich tandem motifs.
Journal
Reference
Authors
Sofeu Feugaing DD, Gotte M, Viola M
Title
More than matrix: the multifaceted role of decorin in cancer.
Journal
Reference
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
Reference
Authors
Teng YH, Aquino RS, Park PW
Title
Molecular functions of syndecan-1 in disease.
Journal
Reference
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
Reference
Authors
Fux L, Ilan N, Sanderson RD, Vlodavsky I
Title
Heparanase: busy at the cell surface.
Journal
Reference
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
Reference
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
Reference
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
Reference
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
Reference
Authors
Nugent MA, Iozzo RV
Title
Fibroblast growth factor-2.
Journal
Reference
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
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
Reference
Authors
Beauvais DM, Rapraeger AC
Title
Syndecans in tumor cell adhesion and signaling.
Journal
Reference
Authors
Morgan MR, Humphries MJ, Bass MD
Title
Synergistic control of cell adhesion by integrins and syndecans.
Journal
Reference
Authors
Filmus J, Capurro M, Rast J
Title
Glypicans.
Journal
Reference
Authors
Filmus J, Capurro M
Title
Glypican-3: a marker and a therapeutic target in hepatocellular carcinoma.
Journal
Reference
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
Authors
Filmus J, Capurro M
Title
The role of glypicans in Hedgehog signaling.
Journal
Reference
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
Reference
Authors
Iozzo RV, Sanderson RD
Title
Proteoglycans in cancer biology, tumour microenvironment and angiogenesis.
Journal
Reference
Authors
Nikitovic D, Katonis P, Tsatsakis A, Karamanos NK, Tzanakakis GN
Title
Lumican, a small leucine-rich proteoglycan.
Journal
Related pathway
hsa04810 Regulation of actin cytoskeleton
KO pathway