The 120 kDa cell-binding fragment of fibronectin up-regulates migration of alphavbeta6-expressing cells by increasing matrix metalloproteinase-2 and -9 secretion.
Changes in the extracellular matrix, integrin expression, and protease secretion occur in wound healing and cancer and these systems are thought to play a crucial role in such processes. In this study, experiments were performed to examine the interaction of epithelial cells with the 120 kDa cell-binding fibronectin fragment. Cell migration was significantly increased in response to the 120 kDa fragment when compared with the full-length molecule, but only in cells overexpressing the beta-6 integrin (VB6). This involved the up-regulation of matrix metalloproteinases (MMPs) 2 and 9, the levels of which are increased in the supernatant from VB6 cells plated on the 120 kDa fragment. Inhibition of MMP activity with both tissue inhibitor of metalloproteinase-1 (TIMP-1) and a chemical inhibitor (Ro32-3580) resulted in a significant reduction in migration on the fibronectin fragment. In vitro this fragment can be generated by incubating full-length fibronectin with purified MMP-9. Expression of the beta6 integrin subunit, which is only seen in wound healing and cancer, enhances the motility of and MMP secretion by epithelial cells in response to the 120 kDa fibronectin fragment. These enzymes can then further degrade fibronectin to generate additional fragments, leading to the creation of a positive feedback loop, which may be of significance in disease processes.
Al-Hazmi
Nadia
N
Oral Biology Division, Oral Basic and Clinical Sciences Department, College of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia.
Thomas
Gareth J
GJ
Speight
Paul M
PM
Whawell
Simon A
SA
D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D005353:Fibronectins / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009062:Mouth Neoplasms / Q000201:enzymology / Q000378:metabolism*; D019030:Receptors, Vitronectin / Q000378:metabolism*
D005353:Fibronectins; D016023:Integrins; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9