Jj. Tomasek et al., GELATINASE-A ACTIVATION IS REGULATED BY THE ORGANIZATION OF THE POLYMERIZED ACTIN CYTOSKELETON, The Journal of biological chemistry, 272(11), 1997, pp. 7482-7487
Gelatinase A (GL-A) is a matrix metalloproteinase (MMP) involved in bo
th connective tissue remodeling and tumor invasion. GL-A activation is
mediated by a membrane-type MMP (MT MMP) that cleaves the GL-A propep
tide. In this study, we examined the role of the actin cytoskeleton in
regulating GL-A activation and MT-MMP-1 expression. Human palmar fasc
ia fibroblasts and human fetal lung fibroblasts were cultured on a pla
nar substratum or within different types of collagen lattices, Fibrobl
asts that formed stress fibers, either on a planar substratum or withi
n an attached collagen lattice, showed reduced GL-A activation compare
d with fibroblasts lacking stress fibers, within either floating or st
ress-released collagen lattices. To determine whether changes in the o
rganization of the actin cy toskeleton could promote GL-A activation,
fibroblasts with stress fibers were treated with cytochalasin D. Withi
n 24 h after treatment, GL-A activation was dramatically increased, As
sociated with this GL-A activation was an increase in MT-MMP-1 mRNA as
determined by Northern blot analysis. Treatment with nocodazole, whic
h induced microtubule depolymerization and cell shape changes without
affecting stress fibers, did not promote GL-A activation. These result
s suggest that the extracellular matrix and the actin cytoskeleton tra
nsduce signals that modulate GL-A activation and regulate tissue remod
eling.