Filamin A controls matrix metalloprotease activity and regulates cell invasion in human fibrosarcoma cells.

Abstract

SummaryFilamins 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.

ASB2α regulates migration of immature dendritic cells

“…Consistent with this finding, FLNa and FLNb suppress matrix degradation and invasion in HT1080 fibrosarcoma cells. 21 Conversely, in macrophages, FLNa stabilizes podosomes, thus enhancing matrix degradation, 19 indicating that the effect of FLNs on podosome formation and matrix degradation is cell type specific. Altogether, our data support the idea that, in immature DCs, ASB2a acts as a positive regulator of ECM invasion through degradation of FLNs.…”

“…Indeed, FLN concentration is a crucial determinant in the stiffness of the actin filament network, 11,12 in cell spreading, [13][14][15] in cell adhesion, 15,16 in cell migration, [17][18][19] and in invasion of cancer cells. 20,21 In this context, deciphering the mechanisms controlling levels of FLN may have broad implications for our understanding of FLN functions in normal cells and dysfunctions in pathological contexts. FLN stability is regulated by proteolysis through cleavages by calpains 22 and ubiquitin-mediated proteasomal degradation controlled by the ASB2 E3 ubiquitin ligases.…”

Complex roles of filamin-A mediated cytoskeleton network in cancer progression

“…Xu et al reported that filamin-A regulates focal adhesion disassembly, and that down-regulation of filamin-A enhances the cleavage of focal adhesion proteins [106]. Furthermore, filamin-A has been shown to play a role in ECM degradation and it has been demonstrated that knockdown of filamin-A increases the expression of matrix metalloproteinase-9 (MMP-9) [107] which induces MMP2 activation [108]. …”

“…Baldassarre et al showed that knockdown of filamin-A in fibrosarcoma increased matrix metalloprotease 2 activity and activation, enhanced the ability of cells to remodel the ECM, and increased cellular invasive potential without significantly altering two-dimensional random cell migration [108]. In addition, using breast cancer cells that over-express ErbB2, Xu et al reported that knockdown of filamin-A promoted cleavage of focal adhesion in cancer cells and stimulated cancer cell migration, invasion, and metastasis.…”

Filamin A regulates the organization and remodeling of the pericellular collagen matrix

“…In many types of connective tissue cells, b1integrinenriched adhesions provide focal sites for ECM remodeling by matrix metalloproteinases (MMPs), a process that is thought to be partly dependent on FLNa (31). Collagen fibrils are also remodeled by phagocytosis (32), an intracellular digestion route for collagen fibrils that involves pericellular fibril fragmentation, internalization, and intracellular digestion by lysosomal cysteine proteinases, such as cathepsins (33, 34).…”