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

Abstract

Extracellular matrix remodeling by cell adhesion-related processes is critical for proliferation and tissue homeostasis, but how adhesions and the cytoskeleton interact to organize the pericellular matrix (PCM) is not understood. We examined the role of the actin-binding protein, filamin A (FLNa), in pericellular collagen remodeling. Compared with wild-type (WT), mice with fibroblast-specific deletion of FLNa exhibited higher density but reduced organization of collagen fibers after increased loading of the periodontal ligament for 2 wk. In cultured fibroblasts, FLNa knockdown (KD) did not affect collagen mRNA, but after 24 h of culture, FLNa WT cells exhibited ∼2-fold higher cell-surface collagen KD cells and 13-fold higher levels of activated β1 integrins. In FLNa WT cells, there was 3-fold more colocalization of talin with pericellular cleaved collagen than in FLNa KD cells. MMP-9 mRNA and protein expression were >2-fold higher in FLNa KD cells than in WT cells. Cathepsin B, which is necessary for intracellular collagen digestion, was >3-fold higher in FLNa WT cells than in KD cells. FLNa WT cells exhibited 2-fold more collagen phagocytosis than KD cells, which involved the FLNa actin-binding domain. Evidently, FLNa regulates PCM remodeling through its effects on degradation pathways that affect the abundance and organization of collagen.-Mezawa, M., Pinto, V. I., Kazembe, M. P., Lee, W. S., McCulloch, C. A. Filamin A regulates the organization and remodeling of the pericellular collagen matrix.

Proteomics reveals the preliminary physiological states of the spotted seal (Phoca largha) pups

“…FLNA is an actin-binding protein that anchors various transmembrane proteins to the actin cytoskeleton to promote cell–cell contact 28 . FLNA has been reported to play a role in neutrophil phagocytosis in humans 29 , and the deletion of FLNA resulted in a twofold reduction in collagen phagocytosis in mice 30 . The rate-limiting step during phagocytosis is the binding of specific adhesion receptors, such as integrins 31 .…”

Mass spectrometry‐based proteomics reveals the distinct nature of the skin proteomes of photoaged compared to intrinsically aged skin

“…Keratin 6A mRNA expression has been shown to be increased with age in sun‐protected human skin , though we did not find a concurrent increase in its binding partner keratin 16 with age. Filamin A is an actin‐binding protein and is known to be important in the pericellular organization of collagen and providing tension to the ECM . Alterations in this protein with age in the skin have not to our knowledge been reported previously, though it is known that mutations in filamin A can lead to cutaneous alterations including fibromas and pigmentary changes .…”

Structural and thermodynamic basis of a frontometaphyseal dysplasia mutation in filamin A

“…This weakened binding of the conjoined repeats to ligands is likely to upset mechanotransduction properties of the entire filamin molecule. This may weaken integrin-extracellular matrix adhesion strength as shown in a recent fibroblast-specific filamin knock-out study (40).…”

“…Mindful of the observation that clustered mutations in the actin binding domain and in repeats 9 -11 and 15-16 also produce FMD (30), this study may serve as a foundational step for elucidating the key signaling functions mediated by filamin A that comprises the fundamental mechanisms leading to a range of filamin-related skeletal diseases. In particular, the altered capacity of filamin autoinhibition by the mutation may affect the strength and dynamics of the extracellular matrix-actin linkage in relation to cell stiffness, adhesion strength (40), etc., which are directly involved in muscle/bone development and thus contribute to the FMD.…”