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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 pp125FAK
Levels Plus Proteoglycan-mediated Apoptosis via Caspases
Yvonne L.
Kapila,
Shaohui
Wang, and
Paul W.
Johnson
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 pp125FAK 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 pp125FAK levels and regulate apoptosis through a
chondroitin sulfate proteoglycan- and possibly 4 integrin-mediated
pathway, which triggers a caspase cascade.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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Copyright © 1999 by the American Society for Biochemistry and Molecular Biology.
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