Identification of Filamin A Mechanobinding Partner I: Smoothelin Specifically Interacts with the Filamin A Mechanosensitive Domain 21

Wang, Lina; Nakamura, Fumihiko

doi:10.1021/acs.biochem.9b00100

Cited by 19 publications

(22 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These novel finding is supported by the work of the group of Nakamura, who found out by SILAC‐based quantitative proteomics that synaptopodin is a potential interaction partner of filamin A. In addition, they identified a filamin A binding motif in the synaptopodin protein sequence by in silico screening 59 …”

Section: Discussionmentioning

confidence: 69%

“…In addition, they identified a filamin A binding motif in the synaptopodin protein sequence by in silico screening. 59 Furthermore, we found that the expression of other actinassociated and podocyte-specific proteins such as ezrin, palladin, fascin-1 and Inf2 were also significantly downregulated in Flna KO podocytes suggesting an important role of filamin A for the regulation of proteins that are involved in actin dynamics as well as for cell adhesion. 45,[60][61][62][63] Pinto and coworkers have shown that mechanoprotection by filamin A occurs via an activation and expression of focal adhesion proteins.…”

Section: F I G U R Ementioning

confidence: 74%

See 1 more Smart Citation

The role of filamins in mechanically stressed podocytes

et al. 2021

View full text Add to dashboard Cite

Glomerular hypertension induces mechanical load to podocytes, often resulting in podocyte detachment and the development of glomerulosclerosis. Although it is well known that podocytes are mechanosensitive, the mechanosensors and mechanotransducers are still unknown. Since filamin A, an actin-binding protein, is already described to be a mechanosensor and mechanotransducer, we hypothesized that filamins could be important for the outside-in signaling as well as the actin cytoskeleton of podocytes under mechanical stress. In this study, we demonstrate that filamin A is the main isoform of the filamin family that is expressed in cultured podocytes. Together with filamin B, filamin A was significantly up-regulated during mechanical stretch (3 days, 0.5 Hz, and 5% extension). To study the role of filamin A in cultured podocytes under mechanical stress, filamin A was knocked down (Flna KD) by specific siRNA.Additionally, we established a filamin A knockout podocyte cell line (Flna KO) by CRISPR/Cas9. Knockdown and knockout of filamin A influenced the expression of synaptopodin, a podocyte-specific protein, focal adhesions as well as the morphology of the actin cytoskeleton. Moreover, the cell motility of Flna KO podocytes was significantly increased. Since the knockout of filamin A has had no effect on cell adhesion of podocytes during mechanical stress, we simultaneously knocked down the expression of filamin A and B. Thereby, we observed a significant loss of podocytes during mechanical stress indicating a compensatory mechanism. Analyzing hypertensive mice kidneys as well as biopsies of patients suffering from diabetic nephropathy, we found an up-regulation of filamin A in podocytes in contrast to the control. In summary, filamin A and B mediate matrix-actin cytoskeleton interactions which are essential for the adaptation of cultured podocyte to mechanical stress.

show abstract

Section: Discussionmentioning

confidence: 69%

Section: F I G U R Ementioning

confidence: 74%

The role of filamins in mechanically stressed podocytes

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Nevertheless, many known AAPs possess uncharacterized ABD (smoothelin, fimbacin, etc.) [76,77] (Figure 3 and Table S1). The structural geometry of AAPs influences their binding strength to actin filaments.…”

Section: How Abps Interact With Actinmentioning

confidence: 99%

“…Although we only listed actin-AAP complexes that currently exist in the protein dat bank, computational analysis has also been used to build a model for some ABPs [75 Nevertheless, many known AAPs possess uncharacterized ABD (smoothelin, fimbacin etc.) [76,77] (Figure 3 and Table S1). The structural geometry of AAPs influences thei binding strength to actin filaments.…”

Section: How Abps Interact With Actinmentioning

confidence: 99%

Actin-Associated Proteins and Small Molecules Targeting the Actin Cytoskeleton

Gao,

Nakamura

2022

IJMS

Self Cite

View full text Add to dashboard Cite

Actin-associated proteins (AAPs) act on monomeric globular actin (G-actin) and polymerized filamentous actin (F-actin) to regulate their dynamics and architectures which ultimately control cell movement, shape change, division; organelle localization and trafficking. Actin-binding proteins (ABPs) are a subset of AAPs. Since actin was discovered as a myosin-activating protein (hence named actin) in 1942, the protein has also been found to be expressed in non-muscle cells, and numerous AAPs continue to be discovered. This review article lists all of the AAPs discovered so far while also allowing readers to sort the list based on the names, sizes, functions, related human diseases, and the dates of discovery. The list also contains links to the UniProt and Protein Atlas databases for accessing further, related details such as protein structures, associated proteins, subcellular localization, the expression levels in cells and tissues, mutations, and pathology. Because the actin cytoskeleton is involved in many pathological processes such as tumorigenesis, invasion, and developmental diseases, small molecules that target actin and AAPs which hold potential to treat these diseases are also listed.

show abstract

“…In 2011, we listed over 90 filamin binding partners including channels, receptors, intracellular signaling molecules, and even transcription factor [2]. In the past ten years, the list of filamin binding partners has been expanded and is still expanding [35,36]. Considering the sequence similarity of filamin isoforms, FLNC likely interacts with most of these numerous binding partners if they are co-expressed, although one binding partners has been shown to only interact with filamin A [37].…”

Section: Flnc Binding Partnersmentioning

confidence: 99%

Structure and Function of Filamin C in the Muscle Z-Disc

Mao

Nakamura

2020

IJMS

Self Cite

View full text Add to dashboard Cite

Filamin C (FLNC) is one of three filamin proteins (Filamin A (FLNA), Filamin B (FLNB), and FLNC) that cross-link actin filaments and interact with numerous binding partners. FLNC consists of a N-terminal actin-binding domain followed by 24 immunoglobulin-like repeats with two intervening calpain-sensitive hinges separating R15 and R16 (hinge 1) and R23 and R24 (hinge-2). The FLNC subunit is dimerized through R24 and calpain cleaves off the dimerization domain to regulate mobility of the FLNC subunit. FLNC is localized in the Z-disc due to the unique insertion of 82 amino acid residues in repeat 20 and necessary for normal Z-disc formation that connect sarcomeres. Since phosphorylation of FLNC by PKC diminishes the calpain sensitivity, assembly, and disassembly of the Z-disc may be regulated by phosphorylation of FLNC. Mutations of FLNC result in cardiomyopathy and muscle weakness. Although this review will focus on the current understanding of FLNC structure and functions in muscle, we will also discuss other filamins because they share high sequence similarity and are better characterized. We will also discuss a possible role of FLNC as a mechanosensor during muscle contraction.

show abstract

Identification of Filamin A Mechanobinding Partner I: Smoothelin Specifically Interacts with the Filamin A Mechanosensitive Domain 21

Cited by 19 publications

References 58 publications

The role of filamins in mechanically stressed podocytes

The role of filamins in mechanically stressed podocytes

Actin-Associated Proteins and Small Molecules Targeting the Actin Cytoskeleton

Structure and Function of Filamin C in the Muscle Z-Disc

Contact Info

Product

Resources

About