ArticleScience signaling2015
Tandem phosphorylation within an intrinsically disordered region regulates ACTN4 function.
Article in Science signaling, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Force-modulated structural landscape of the catch bonding F-actin crosslinker α-actinin-4.bioRxiv : the preprint server for biology · 2026Article
- Characterization of ACTN4 as a novel antiviral target against SARS-CoV-2.Signal transduction and targeted therapy · 2024Article
- Protein tyrosine phosphatase 1B is a regulator of alpha-actinin4 in the glomerular podocyte.Biochimica et biophysica acta. Molecular cell research · 2024Article
- Accessing isotopically labeled proteins containing genetically encoded phosphoserine for NMR with optimized expression conditions.The Journal of biological chemistry · 2022Article
- Force- and cell state-dependent recruitment of Piezo1 drives focal adhesion dynamics and calcium entry.Science advances · 2022Article
- α-Actinin-4 recruits Shp2 into focal adhesions to potentiate ROCK2 activation in podocytes.Life science alliance · 2022Article
- The Importance of Alpha-Actinin Proteins in Platelet Formation and Function, and Their Causative Role in Congenital Macrothrombocytopenia.International journal of molecular sciences · 2021Review
- Manipulation of Focal Adhesion Signaling by Pathogenic Microbes.International journal of molecular sciences · 2021Review
- Article
- Cytoskeletal Remodeling in Cancer.Biology · 2020Review
- Phosphorylation of key podocyte proteins and the association with proteinuric kidney disease.American journal of physiology. Renal physiology · 2020Review
- Phosphorylation of ACTN4 Leads to Podocyte Vulnerability and Proteinuric Glomerulosclerosis.Journal of the American Society of Nephrology : JASN · 2020Article
- Focal segmental glomerulosclerosis ACTN4 mutants binding to actin: regulation by phosphomimetic mutations.Scientific reports · 2019Article
- Tyro3-mediated phosphorylation of ACTN4 at tyrosines is FAK-dependent and decreases susceptibility to cleavage by m-Calpain.The international journal of biochemistry & cell biology · 2018Article
- Concerted millisecond timescale dynamics in the intrinsically disordered carboxyl terminus of γ-tubulin induced by mutation of a conserved tyrosine residue.Protein science : a publication of the Protein Society · 2018Article
- Phosphorylation of multiple sites within an acidic region of Alcadein α is required for kinesin-1 association and Golgi exit of Alcadein α cargo.Molecular biology of the cell · 2017Article
- The fifth sense: Mechanosensory regulation of alpha-actinin-4 and its relevance for cancer metastasis.Seminars in cell & developmental biology · 2017Review
- Multisite Phosphorylation Modulates the T Cell Receptor ζ-Chain Potency but not the Switchlike Response.Biophysical journal · 2016Article
- Reductionism Is Dead: Long Live Reductionism! Systems Modeling Needs Reductionist Experiments.Biophysical journal · 2016Article
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Authors and funding
6 authors.
Funding
Abstract
Phosphorylated residues occur preferentially in the intrinsically disordered regions of eukaryotic proteins. In the disordered amino-terminal region of human α-actinin-4 (ACTN4), Tyr(4) and Tyr(31) are phosphorylated in cells stimulated with epidermal growth factor (EGF), and a mutant with phosphorylation-mimicking mutations of both tyrosines exhibits reduced interaction with actin in vitro. Cleavage of ACTN4 by m-calpain, a protease that in motile cells is predominantly activated at the rear, removes the Tyr(4) site. We found that introducing a phosphomimetic mutation at only Tyr(31) was sufficient to inhibit the interaction with actin in vitro. However, molecular dynamics simulations predicted that Tyr(31) is mostly buried and that phosphorylation of Tyr(4) would increase the solvent exposure and thus kinase accessibility of Tyr(31). In fibroblast cells, EGF stimulation increased tyrosine phosphorylation of a mutant form of ACTN4 with a phosphorylation-mimicking residue at Tyr(4), whereas a truncated mutant representing the product of m-calpain cleavage exhibited EGF-stimulated tyrosine phosphorylation at a background amount similar to that observed for a double phosphomimetic mutant of Tyr(4) and Tyr(31). We also found that inhibition of the receptor tyrosine kinases of the TAM family, such as AXL, blocked EGF-stimulated tyrosine phosphorylation of ACTN4. Mathematical modeling predicted that the kinetics of phosphorylation at Tyr(31) can be dictated by the kinase affinity for Tyr(4). This study suggests that tandem-site phosphorylation within intrinsically disordered regions provides a mechanism for a site to function as a switch to reveal a nearby function-regulating site.
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