Interference of tenascin-C with syndecan-4 binding to fibronectin blocks cell adhesion and stimulates tumor cell proliferation.
Tenascin-C is an adhesion-modulatory extracellular matrix molecule that is highly expressed in tumors. To investigate the effect of tenascin-C on tumor cells, we analyzed its antiadhesive nature and effect on tumor cell proliferation in a fibronectin context. Glioblastoma and breast carcinoma cell adhesion was compromised by a mixed fibronectin/tenascin-C substratum, which concomitantly caused increased tumor-cell proliferation. We identified the antiadhesive mechanism as a specific interference of tenascin-C with cell binding to the HepII/syndecan-4 site in fibronectin through direct binding of tenascin-C to the 13th fibronectin type III repeat (FNIII13). Cell adhesion and proliferation levels were restored by the addition of FNIII13. Overexpression of syndecan-4, but not syndecan-1 or -2, reverted the cell adhesion defect of tenascin-C. We characterized FNIII13 as the binding site for syndecan-4. Thus we describe a novel mechanism by which tenascin-C impairs the adhesive function of fibronectin through binding to FNIII13, thereby inhibiting the coreceptor function of syndecan-4 in fibronectin-induced integrin signaling.
Huang
W
W
Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland.
Chiquet-Ehrismann
R
R
Moyano
J V
JV
Garcia-Pardo
A
A
Orend
G
G
D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002645:Chickens; D006224:Cricetinae; D005353:Fibronectins / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism*; D017469:Receptors, Fibronectin / Q000096:biosynthesis; D053671:Syndecan-4; D019063:Tenascin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D005353:Fibronectins; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D011509:Proteoglycans; D017469:Receptors, Fibronectin; C508304:SDC4 protein, human; D053671:Syndecan-4; D019063:Tenascin