• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of biochemjBJ Latest papers and much more!
Biochem J. Apr 15, 2002; 363(Pt 2): 201–209.
PMCID: PMC1222468

The role of syndecan-2 in regulation of actin-cytoskeletal organization of Lewis lung carcinoma-derived metastatic clones.


Syndecans, a family of transmembrane heparan sulphate proteoglycans, contribute to various biological processes, including adhesion, motility, proliferation, differentiation and morphogenesis. We document here the involvement of syndecan-2 acting alone or co-operatively with integrin alpha5beta1, for regulation of actin-cytoskeletal organization on cell adhesion to fibronectin, using fibronectin-recombinant polypeptides containing the ligands for either or both of these receptors as substrata. Lewis lung carcinoma-derived low-metastatic P29 cells binding to the substrata by both receptors formed actin stress fibres, whereas those binding by syndecan-2 or integrin alpha5beta1 alone formed filopodia or cortex actin. In contrast, higher metastatic LM66-H11 cells formed cortex actin even on substrata containing both ligands. Northern-blot and flow-cytometric analyses revealed that syndecan-2 expression in LM66-H11 cells was significantly lower (1/4.5 in mRNA and 1/8 in cell-surface expression) than in P29 cells, whereas expression levels of integrin alpha5beta1 and other syndecans were similar in both cell types. These results suggest that the failure of LM66-H11 to form stress fibres is due to a lower expression of syndecan-2 than that due to a threshold for its function. This was confirmed by the finding that overexpression of syndecan-2 by transfection of its cDNA into LM66-H11 cells caused the formation of stress fibres on the fibronectin substratum. These in vitro cellular responses of the two clones might reflect their in vivo situation in primary tumours in which P29 cells with a stroma-inducing capacity were immediately surrounded by fibronectin-rich matrix formed by the induced stromal cells, whereas LM66-H11 cells without such capacity were not surrounded by a similar matrix.

Full Text

The Full Text of this article is available as a PDF (293K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Adams JC, Watt FM. Regulation of development and differentiation by the extracellular matrix. Development. 1993 Apr;117(4):1183–1198. [PubMed]
  • Grinnell F. Wound repair, keratinocyte activation and integrin modulation. J Cell Sci. 1992 Jan;101(Pt 1):1–5. [PubMed]
  • Chiquet-Ehrismann R. Tenascin and other adhesion-modulating proteins in cancer. Semin Cancer Biol. 1993 Oct;4(5):301–310. [PubMed]
  • Ekblom M, Klein G, Mugrauer G, Fecker L, Deutzmann R, Timpl R, Ekblom P. Transient and locally restricted expression of laminin A chain mRNA by developing epithelial cells during kidney organogenesis. Cell. 1990 Jan 26;60(2):337–346. [PubMed]
  • Prieto AL, Jones FS, Cunningham BA, Crossin KL, Edelman GM. Localization during development of alternatively spliced forms of cytotactin mRNA by in situ hybridization. J Cell Biol. 1990 Aug;111(2):685–698. [PMC free article] [PubMed]
  • Damsky CH, Werb Z. Signal transduction by integrin receptors for extracellular matrix: cooperative processing of extracellular information. Curr Opin Cell Biol. 1992 Oct;4(5):772–781. [PubMed]
  • Huhtala P, Humphries MJ, McCarthy JB, Tremble PM, Werb Z, Damsky CH. Cooperative signaling by alpha 5 beta 1 and alpha 4 beta 1 integrins regulates metalloproteinase gene expression in fibroblasts adhering to fibronectin. J Cell Biol. 1995 May;129(3):867–879. [PMC free article] [PubMed]
  • Pierschbacher MD, Ruoslahti E. Cell attachment activity of fibronectin can be duplicated by small synthetic fragments of the molecule. Nature. 1984 May 3;309(5963):30–33. [PubMed]
  • Hynes RO. Integrins: a family of cell surface receptors. Cell. 1987 Feb 27;48(4):549–554. [PubMed]
  • Miyamoto S, Katz BZ, Lafrenie RM, Yamada KM. Fibronectin and integrins in cell adhesion, signaling, and morphogenesis. Ann N Y Acad Sci. 1998 Oct 23;857:119–129. [PubMed]
  • Miyamoto S, Akiyama SK, Yamada KM. Synergistic roles for receptor occupancy and aggregation in integrin transmembrane function. Science. 1995 Feb 10;267(5199):883–885. [PubMed]
  • Miyamoto S, Teramoto H, Coso OA, Gutkind JS, Burbelo PD, Akiyama SK, Yamada KM. Integrin function: molecular hierarchies of cytoskeletal and signaling molecules. J Cell Biol. 1995 Nov;131(3):791–805. [PMC free article] [PubMed]
  • Rapraeger AC. Syndecan-regulated receptor signaling. J Cell Biol. 2000 May 29;149(5):995–998. [PMC free article] [PubMed]
  • Woods A, Couchman JR. Syndecans: synergistic activators of cell adhesion. Trends Cell Biol. 1998 May;8(5):189–192. [PubMed]
  • Couchman JR, Woods A. Syndecan-4 and integrins: combinatorial signaling in cell adhesion. J Cell Sci. 1999 Oct;112(Pt 20):3415–3420. [PubMed]
  • Saoncella S, Echtermeyer F, Denhez F, Nowlen JK, Mosher DF, Robinson SD, Hynes RO, Goetinck PF. Syndecan-4 signals cooperatively with integrins in a Rho-dependent manner in the assembly of focal adhesions and actin stress fibers. Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):2805–2810. [PMC free article] [PubMed]
  • Oh ES, Woods A, Couchman JR. Syndecan-4 proteoglycan regulates the distribution and activity of protein kinase C. J Biol Chem. 1997 Mar 28;272(13):8133–8136. [PubMed]
  • Oh ES, Woods A, Couchman JR. Multimerization of the cytoplasmic domain of syndecan-4 is required for its ability to activate protein kinase C. J Biol Chem. 1997 May 2;272(18):11805–11811. [PubMed]
  • Oh ES, Woods A, Lim ST, Theibert AW, Couchman JR. Syndecan-4 proteoglycan cytoplasmic domain and phosphatidylinositol 4,5-bisphosphate coordinately regulate protein kinase C activity. J Biol Chem. 1998 Apr 24;273(17):10624–10629. [PubMed]
  • Grootjans JJ, Zimmermann P, Reekmans G, Smets A, Degeest G, Dürr J, David G. Syntenin, a PDZ protein that binds syndecan cytoplasmic domains. Proc Natl Acad Sci U S A. 1997 Dec 9;94(25):13683–13688. [PMC free article] [PubMed]
  • Cohen AR, Woods DF, Marfatia SM, Walther Z, Chishti AH, Anderson JM, Wood DF. Human CASK/LIN-2 binds syndecan-2 and protein 4.1 and localizes to the basolateral membrane of epithelial cells. J Cell Biol. 1998 Jul 13;142(1):129–138. [PMC free article] [PubMed]
  • Gao Y, Li M, Chen W, Simons M. Synectin, syndecan-4 cytoplasmic domain binding PDZ protein, inhibits cell migration. J Cell Physiol. 2000 Sep;184(3):373–379. [PubMed]
  • Ethell IM, Hagihara K, Miura Y, Irie F, Yamaguchi Y. Synbindin, A novel syndecan-2-binding protein in neuronal dendritic spines. J Cell Biol. 2000 Oct 2;151(1):53–68. [PMC free article] [PubMed]
  • 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. 2000 Jan;113(Pt 2):315–324. [PubMed]
  • Kusano Y, Oguri K, Nagayasu Y, Munesue S, Ishihara M, Saiki I, Yonekura H, Yamamoto H, Okayama M. Participation of syndecan 2 in the induction of stress fiber formation in cooperation with integrin alpha5beta1: structural characteristics of heparan sulfate chains with avidity to COOH-terminal heparin-binding domain of fibronectin. Exp Cell Res. 2000 May 1;256(2):434–444. [PubMed]
  • Itano N, Oguri K, Nakanishi H, Okayama M. Membrane-intercalated proteoglycan of a stroma-inducing clone from Lewis lung carcinoma binds to fibronectin via its heparan sulfate chains. J Biochem. 1993 Dec;114(6):862–873. [PubMed]
  • Itano N, Oguri K, Nagayasu Y, Kusano Y, Nakanishi H, David G, Okayama M. Phosphorylation of a membrane-intercalated proteoglycan, syndecan-2, expressed in a stroma-inducing clone from a mouse Lewis lung carcinoma. Biochem J. 1996 May 1;315(Pt 3):925–930. [PMC free article] [PubMed]
  • Nakanishi H, Takenaga K, Oguri K, Yoshida A, Okayama M. Morphological characteristics of tumours formed by Lewis lung carcinoma-derived cloned cell lines with different metastatic potentials: structural differences in their basement membranes formed in vivo. Virchows Arch A Pathol Anat Histopathol. 1992;420(2):163–170. [PubMed]
  • Nakanishi H, Oguri K, Yoshida K, Itano N, Takenaga K, Kazama T, Yoshida A, Okayama M. Structural differences between heparan sulphates of proteoglycan involved in the formation of basement membranes in vivo by Lewis-lung-carcinoma-derived cloned cells with different metastatic potentials. Biochem J. 1992 Nov 15;288(Pt 1):215–224. [PMC free article] [PubMed]
  • Nakanishi H, Oguri K, Takenaga K, Hosoda S, Okayama M. Differential fibrotic stromal responses of host tissue to low- and high-metastatic cloned Lewis lung carcinoma cells. Lab Invest. 1994 Mar;70(3):324–332. [PubMed]
  • Narumi K, Satoh K, Isemura M, Sakai T, Abe T, Kikuchi T, Sindoh S, Motomiya M, Oguri K, Okayama M. Difference in laminin expression between high and low metastatic cell clones derived from murine Lewis lung carcinoma. Cell Struct Funct. 1993 Jun;18(3):183–187. [PubMed]
  • Kornblihtt AR, Umezawa K, Vibe-Pedersen K, Baralle FE. Primary structure of human fibronectin: differential splicing may generate at least 10 polypeptides from a single gene. EMBO J. 1985 Jul;4(7):1755–1759. [PMC free article] [PubMed]
  • Yamamura M, Uyemura K, Deans RJ, Weinberg K, Rea TH, Bloom BR, Modlin RL. Defining protective responses to pathogens: cytokine profiles in leprosy lesions. Science. 1991 Oct 11;254(5029):277–279. [PubMed]
  • Yonekura H, Migita H, Sakurai S, Wang H, Harada S, Abedin MJ, Yamagishi S, Yamamoto H. Antisense display--a method for functional gene screening: evaluation in a cell-free system and isolation of angiogenesis-related genes. Nucleic Acids Res. 1999 Jul 1;27(13):2591–2600. [PMC free article] [PubMed]
  • Bernfield M, Götte M, Park PW, Reizes O, Fitzgerald ML, Lincecum J, Zako M. Functions of cell surface heparan sulfate proteoglycans. Annu Rev Biochem. 1999;68:729–777. [PubMed]
  • Marynen P, Zhang J, Cassiman JJ, Van den Berghe H, David G. Partial primary structure of the 48- and 90-kilodalton core proteins of cell surface-associated heparan sulfate proteoglycans of lung fibroblasts. Prediction of an integral membrane domain and evidence for multiple distinct core proteins at the cell surface of human lung fibroblasts. J Biol Chem. 1989 Apr 25;264(12):7017–7024. [PubMed]
  • Mizuno K, Inoue H, Hagiya M, Shimizu S, Nose T, Shimohigashi Y, Nakamura T. Hairpin loop and second kringle domain are essential sites for heparin binding and biological activity of hepatocyte growth factor. J Biol Chem. 1994 Jan 14;269(2):1131–1136. [PubMed]
  • Filla MS, Dam P, Rapraeger AC. The cell surface proteoglycan syndecan-1 mediates fibroblast growth factor-2 binding and activity. J Cell Physiol. 1998 Mar;174(3):310–321. [PubMed]
  • Pye DA, Vives RR, Turnbull JE, Hyde P, Gallagher JT. Heparan sulfate oligosaccharides require 6-O-sulfation for promotion of basic fibroblast growth factor mitogenic activity. J Biol Chem. 1998 Sep 4;273(36):22936–22942. [PubMed]
  • Echtermeyer F, Baciu PC, Saoncella S, Ge Y, Goetinck PF. Syndecan-4 core protein is sufficient for the assembly of focal adhesions and actin stress fibers. J Cell Sci. 1999 Oct;112(Pt 20):3433–3441. [PubMed]
  • Ishiguro K, Kadomatsu K, Kojima T, Muramatsu H, Tsuzuki S, Nakamura E, Kusugami K, Saito H, Muramatsu T. Syndecan-4 deficiency impairs focal adhesion formation only under restricted conditions. J Biol Chem. 2000 Feb 25;275(8):5249–5252. [PubMed]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Gene
    Gene links
  • GEO Profiles
    GEO Profiles
    Related GEO records
  • HomoloGene
    HomoloGene links
  • MedGen
    Related information in MedGen
  • Pathways + GO
    Pathways + GO
    Pathways, annotations and biological systems (BioSystems) that cite the current article.
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...