ArticleBlood2015
Filamin A interaction with the CXCR4 third intracellular loop regulates endocytosis and signaling of WT and WHIM-like receptors.
Article in Blood, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 27 citations in OpenAlex.
- Physical interaction with Ephrin B1 promotes CXCR4 intracellular localization and oncogenic potential.Cellular and molecular life sciences : CMLS · 2026Article
- Immunological synapse: structures, molecular mechanisms and therapeutic implications in disease.Signal transduction and targeted therapy · 2025Review
- The complex nature of CXCR4 mutations in WHIM syndrome.Frontiers in immunology · 2024Review
- Distinct and targetable role of calcium-sensing receptor in leukaemia.Nature communications · 2023Article
- Altered CXCR4 dynamics at the cell membrane impairs directed cell migration in WHIM syndrome patients.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Review
- Aberrant CXCR4 Signaling at Crossroad of WHIM Syndrome and Waldenstrom's Macroglobulinemia.International journal of molecular sciences · 2020Review
- CCR5 deficiency impairs CD4The EMBO journal · 2020Article
- Enhanced Bone Marrow Homing of Natural Killer Cells Following mRNA Transfection With Gain-of-Function Variant CXCR4Frontiers in immunology · 2019Article
- In Silico Studies Targeting G-protein Coupled Receptors for Drug Research Against Parkinson's Disease.Current neuropharmacology · 2018Article
- Pathogenesis, diagnosis and therapeutic strategies in WHIM syndrome immunodeficiency.Expert opinion on orphan drugs · 2017Article
- Dysregulation of Chemokine/Chemokine Receptor Axes and NK Cell Tissue Localization during Diseases.Frontiers in immunology · 2016Review
- G protein-coupled receptors directly bind filamin A with high affinity and promote filamin phosphorylation.Biochemistry · 2015Article
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Authors and funding
7 authors at 4 institutions in 2 countries.
Funding
Abstract
Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare congenital immunodeficiency often caused by mutations in the last 10 to 19 C-terminal amino acids of CXCR4. These mutations impair CXCR4 internalization and increase responsiveness to CXCL12. The CXCR4 C-terminal domain (C-tail) also has a binding site for the actin-binding protein filamin A (FLNA); it is not known whether FLNA binds to WHIM CXCR4 mutants or whether this interaction is implicated in the hyperfunction of these receptors. Here we show that, in addition to interacting with the CXCR4 C-tail, FLNA interacted with a region in the receptor third intracellular loop (ICL3) spanning amino acids 238 to 246. This interaction involved specific FLNA repeats and was sensitive to Rho kinase inhibition. Deletion of the 238-246 motif accelerated CXCL12-induced wild-type (WT) receptor endocytosis but enabled CXCL12-mediated endocytosis and normalized signaling by the WHIM-associated receptor CXCR4(R334X). CXCL12 stimulation triggered CXCR4(R334X) internalization in FLNA-deficient M2 cells but not in the FLNA-expressing M2 subclone A7; this suggests a role for FLNA in stabilization of WHIM-like CXCR4 at the cell surface. FLNA increased β-arrestin2 binding to CXCR4(R334X) in vivo, which provides a molecular basis for FLNA-mediated hyperactivation of WHIM receptor signaling. We propose that FLNA interaction with ICL3 is central for endocytosis and signaling of WT and WHIM-like CXCR4 receptors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.