Fibronectin growth factor-binding domains are required for fibroblast survival.
Fibronectin (FN) is required for embryogenesis, morphogenesis, and wound repair, and its Arg-Gly-Asp-containing central cell-binding domain (CCBD) is essential for mesenchymal cell survival and growth. Here, we demonstrate that FN contains three growth factor-binding domains (FN-GFBDs) that bind platelet-derived growth factor-BB (PDGF-BB), a potent fibroblast survival and mitogenic factor. These sites bind PDGF-BB with dissociation constants of 10-100 nM. FN-null cells cultured on recombinant CCBD (FNIII(8-11)) without a FN-GFBD demonstrated minimal metabolism and underwent autophagy at 24 hours, followed by apoptosis at 72 hours, even in the presence of PDGF-BB. In contrast, FN-null cells plated on FNIII(8-11) contiguous with FN-GFBD survived without, and proliferated with, PDGF-BB. FN-null cell survival on FNIII(8-11) and noncontiguous arrays of FN-GFBDs required these domains to be adsorbed on the same surface, suggesting the existence of a mesenchymal cell-extracellular matrix synapse. Thus, fibroblast survival required GF stimulation in the presence of a FN-GFBD, as well as adhesion to FN through the CCBD. The findings that fibroblast survival is dependent on FN-GFBD underscore the critical importance of pericellular matrix for cell survival and have significant implications for cutaneous wound healing and regeneration.
Lin
Fubao
F
Department of Biomedical Engineering, Stony Brook University, Stony Brook, New York, USA.
Ren
Xiang-Dong
XD
Pan
Zhi
Z
Macri
Lauren
L
Zong
Wei-Xing
WX
Tonnesen
Marcia G
MG
Rafailovich
Miriam
M
Bar-Sagi
Dafna
D
Clark
Richard A F
RA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D000077214:Becaplermin; D001665:Binding Sites / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology* / Q000502:physiology; D005353:Fibronectins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D010982:Platelet-Derived Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D020574:Proto-Oncogene Proteins c-sis; D014945:Wound Healing / Q000502:physiology*
D005353:Fibronectins; D008565:Membrane Proteins; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin
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