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J Biol Chem, Vol. 274, Issue 43, 30906-30913, October 22, 1999

Mutations in the Heparin Binding Domain of Fibronectin in Cooperation with the V Region Induce Decreases in pp125^FAK Levels Plus Proteoglycan-mediated Apoptosis via Caspases

From the Department of Stomatology, School of Dentistry, University of California, San Francisco, California 94143-0512

Intact fibronectin (FN) protects cells from apoptosis. When FN is fragmented, specific domains induce proteinase expression in fibroblasts. However, it is not known whether specific domains of FN can also regulate apoptosis. We exposed fibroblasts to four recombinant FN fragments and then assayed for apoptosis using criteria of cellular shape change, condensed nuclear morphology, and DNA fragmentation. The fragments extended from the RGD-containing repeat III10 to III15; they included (V⁺) or excluded (V) the alternatively spliced V region and contained either a mutated (H) or an unmutated (H⁺) heparin binding domain. Only the V⁺H fragment triggered decreases in pp125^FAK levels and apoptosis, which was rescued by intact FN and inhibitors of caspase-1 and caspase-3. This apoptotic mechanism was mediated by a chondroitin sulfate proteoglycan, since treating cells with chondroitin sulfate or chondroitinase reversed the apoptotic cell shape changes. The 4 integrin receptor may also be involved, since using a blocking antibody to 4 alone induced apoptotic cell shape changes, whereas co-treatment with this antibody plus V⁺H⁺ reversed these effects. These results demonstrate that the V and heparin binding domains of FN modulate pp125^FAK levels and regulate apoptosis through a chondroitin sulfate proteoglycan- and possibly 4 integrin-mediated pathway, which triggers a caspase cascade.

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