Filamin
Description
Cytoskeletal Organization
Filamins convert actin filaments into orthogonal networks or bundles, depending on their concentration relative to actin . At low molar ratios (1:200–1:50), they form 3D gels; at higher ratios (>1:20), they induce bundling .
Mechanosensing and Signaling
Filamins act as scaffolding hubs, interacting with >30 proteins, including integrins, ion channels, and signaling molecules . For example:
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Vascular endothelial growth factor (VEGF) signaling: Filamin B regulates VEGF-induced angiogenesis by modulating actin dynamics in endothelial cells .
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Cell migration: Filamin A phosphorylation at S2152 influences focal adhesion turnover and cancer metastasis .
Muscle Integrity
Filamin C stabilizes Z-discs in muscle sarcomeres. Drosophila studies show filamin deficiency causes Z-disc rupture under mechanical stress, leading to myofibril damage .
Post-Translational Modifications (PTMs) and Disease Links
Filamin A undergoes diverse PTMs that regulate its function and stability:
Table 2: Key PTMs of Filamin A and Pathological Associations
Cancer Therapeutics
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Thioazo compounds: Molecular docking studies identify compound 3 as a potent Filamin A inhibitor, showing superior binding affinity (−6.6 kcal/mol) compared to doxorubicin (−5.5 kcal/mol) .
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Artemetin: A flavonoid that disrupts Filamin A/B conformation, inducing cytoskeletal disassembly in HeLa cells .
Developmental Disorders
Filamin A mediates embryonic palatal fusion by linking RhoA and TGF-β signaling. Dysregulation correlates with cleft palate pathogenesis .
Future Research Directions
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Isoform-specific PTM mapping: Clarify how phosphorylation sites vary across cell types and disease states .
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Mechanotransduction pathways: Explore filamin’s role in force-dependent signaling in muscle and cancer .
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Drug development: Optimize thioazo derivatives and artemetin analogs for clinical trials .
Product Specs
Q&A
Filamin, a crucial actin-binding protein involved in cytoskeletal organization and cellular signaling, presents numerous research avenues. Below are FAQs tailored for academic researchers, categorized into basic and advanced questions, with methodological guidance and data-driven insights.
Advanced Research Questions
How to resolve contradictory data on Filamin's role in cancer metastasis?
| Approach | Application |
|---|---|
| Multi-omics integration | Combine RNA-seq (Filamin expression) with proteomics (signaling pathways) to identify context-dependent roles. |
| In vivo modeling | Use orthotopic xenografts in mice with tissue-specific Filamin deletion. |
| Single-cell analysis | Profile metastatic vs. primary tumor cells for Filamin interactome variations. |
What strategies identify Filamin's phosphorylation-dependent interactions?
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Phos-tag SDS-PAGE: Resolve phosphorylated Filamin isoforms.
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Co-immunoprecipitation (Co-IP) with anti-Filamin antibodies in stimulated vs. unstimulated cells.
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Kinase inhibitor screens to map upstream regulators (e.g., PAK1, ROCK).
How to design studies analyzing Filamin mutations in genetic disorders?
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Patient-derived iPSCs: Differentiate into affected cell types (e.g., cardiomyocytes for filaminopathy).
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Molecular dynamics simulations: Predict structural impacts of mutations (e.g., FLNA missense variants).
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Force spectroscopy: Compare mutant vs. wild-type Filamin’s mechanical stability.
Methodological Considerations for Data Contradictions
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Reproducibility checks: Replicate experiments across multiple cell lines or model organisms.
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Meta-analysis: Aggregate published datasets to identify consensus patterns (e.g., Filamin’s role in TGF-β signaling).
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Controls: Include isogenic controls in mutation studies and validate antibodies via siRNA knockdown.
Product Science Overview
Filamin proteins are composed of an actin-binding domain at their N-terminus, followed by 24 immunoglobulin-like repeat modules, each consisting of approximately 95 amino acids . These repeats are interspersed with two hinge regions, located between repeats 15-16 and 23-24 . The hinge regions allow for the cleavage of filamin into smaller fragments, which can then participate in different cellular functions.
There are three main types of filamin proteins in mammals:
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Filamin A (FLNA): This protein is involved in various cellular processes, including the stabilization of the actin cytoskeleton and the anchoring of membrane proteins . FLNA plays a significant role in the cardiovascular system, particularly in platelet function and wound repair . Mutations in the FLNA gene can lead to conditions such as macrothrombocytopenia, which affects the production of giant platelets necessary for healing .
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Filamin B (FLNB): Similar to FLNA, FLNB is involved in the organization of the actin cytoskeleton and the regulation of cell shape and migration. It also plays a role in skeletal development and has been implicated in various skeletal disorders.
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Filamin C (FLNC): This protein is primarily found in cardiac and skeletal muscle tissues . FLNC contributes to the structure of cardiac muscle by being a part of the Z-disk proteins, which are abundant in both cardiac and skeletal muscle tissues . Mutations in the FLNC gene can lead to cardiomyopathies, such as hypertrophic cardiomyopathy (HCM) and restrictive cardiomyopathy (RCM) .
Filamins serve multiple functions within the cell:
- Actin Crosslinking: Filamins crosslink actin filaments into orthogonal networks, providing structural support to the cell .
- Signal Transduction: They act as scaffolds for various signaling proteins, including tyrosine kinases, GTPases, and phosphatases . This allows them to connect adhesive receptors, such as integrins, to signaling pathways and the cytoskeleton .
- Cell Migration: By remodeling the actin cytoskeleton, filamins facilitate cell migration, which is essential for processes like wound healing and immune responses .
Mutations in filamin genes can lead to various diseases and disorders:
- Cardiomyopathies: Mutations in the FLNC gene are associated with cardiomyopathies, which can affect the heart’s ability to pump blood effectively .
- Skeletal Disorders: FLNB mutations can result in skeletal abnormalities and developmental disorders.
- Platelet Function: FLNA mutations can disrupt platelet function, leading to conditions like macrothrombocytopenia .
