Filamins are an important family of
actin-binding proteins that, in addition to bundling actin filaments, link cell surface adhesion
proteins, signaling receptors and channels to the actin cytoskeleton, and serve as scaffolds for an array of
intracellular signaling proteins.
Filamins are known to regulate the actin cytoskeleton, act as mechanosensors that modulate tissue responses to matrix density, control cell motility and inhibit activation of
integrin adhesion receptors. In this study, we extend the repertoire of
filamin activities to include control of extracellular matrix (ECM) degradation. We show that knockdown of
filamin increases
matrix metalloproteinase (
MMP) activity and induces MMP2 activation, enhancing the ability of cells to remodel the ECM and increasing their invasive potential, without significantly altering two-dimensional random cell migration. We further show that within
filamin A, the actin-binding domain is necessary, but not sufficient, to suppress the ECM degradation seen in
filamin-A-knockdown cells and that dimerization and
integrin binding are not required.
Filamin mutations are associated with
neuronal migration disorders and a range of congenital malformations characterized by skeletal dysplasia and various combinations of cardiac, craniofacial and intestinal anomalies. Furthermore, in breast
cancers loss of
filamin A has been correlated with increased metastatic potential. Our data suggest that effects on ECM remodeling and cell invasion should be considered when attempting to provide cellular explanations for the physiological and pathological effects of altered
filamin expression or
filamin mutations.