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

Massimiliano Baldassarre, Ziba Razinia, Nina N Brahme, Roberto Buccione, David A Calderwood

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)3858-3869
Number of pages12
JournalJournal of Cell Science
Volume125
Issue number16
DOIs
Publication statusPublished - 15 Aug 2012

Keywords

  • actins
  • cell adhesion
  • cell line, tumor
  • cell movement
  • contractile proteins
  • enzyme activation
  • extracellular matrix
  • fibrosarcoma
  • gene knockdown techniques
  • humans
  • integrins
  • matrix metalloproteinase 14
  • matrix metalloproteinase 2
  • microfilament proteins
  • neoplasm invasiveness
  • phenotype
  • protein structure, tertiary

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