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Cited by 9Cellular Mechanics and InteractionsProtein Kinase Regulation and GTPase SignalingKruppel-like factors research

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Cyclase-associated protein 2 (CAP2) controls MRTF-A localization and SRF activity in mouse embryonic fibroblasts

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Kepser, Lara-Jane, Khudayberdiev, Sharof, Hinojosa, Laura Soto, Macchi, Chiara, Ruscica, Massimiliano, Marcello, Elena, Culmsee, Carsten, Grosse, Robert, Rust, Marco B.·2021·Scientific Reports
DOI 10.1038/s41598-021-84213-wPMC PMC7910472

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Abstract

Recent studies identified cyclase-associated proteins (CAPs) as important regulators of actin dynamics that control assembly and disassembly of actin filaments (F-actin). While these studies significantly advanced our knowledge of their molecular functions, the physiological relevance of CAPs largely remained elusive. Gene targeting in mice implicated CAP2 in heart physiology and skeletal muscle development. Heart defects in CAP2 mutant mice were associated with altered activity of serum response factor (SRF), a transcription factor involved in multiple biological processes including heart function, but also skeletal muscle development. By exploiting mouse embryonic fibroblasts (MEFs) from CAP2 mutant mice, we aimed at deciphering the CAP2-dependent mechanism relevant for SRF activity. Reporter assays and mRNA quantification by qPCR revealed reduced SRF-dependent gene expression in mutant MEFs. Reduced SRF activity in CAP2 mutant MEFs was associated with altered actin turnover, a shift in the actin equilibrium towards monomeric actin (G-actin) as well as and reduced nuclear levels of myocardin-related transcription factor A (MRTF-A), a transcriptional SRF coactivator that is shuttled out of the nucleus and, hence, inhibited upon G-actin binding. Moreover, pharmacological actin manipulation with jasplakinolide restored MRTF-A distribution in mutant MEFs. Our data are in line with a model in which CAP2 controls the MRTF-SRF pathway in an actin-dependent manner. While MRTF-A localization and SRF activity was impaired under basal conditions, serum stimulation induced nuclear MRTF-A translocation and SRF activity in mutant MEFs similar to controls. In summary, our data revealed that in MEFs CAP2 controls basal MRTF-A localization and SRF activity, while it was dispensable for serum-induced nuclear MRTF-A translocation and SRF stimulation.

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Metadata

Authors
Kepser, L.-J., Khudayberdiev, S., Hinojosa, L. S., Macchi, C., Ruscica, M., Marcello, E., Culmsee, C., Grosse, R., & Rust, M. B.
Affiliations
  • Philipps University of Marburg (DE)
  • University of Milan (IT)
Corresponding author
Rust, Marco B.
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2021-02-26
Volume
11
Issue
1
Pages
4789-4789
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-021-84213-w
PMC
PMC7910472
OpenAlex
W3130979346
Cited by
9
References
2
Citations by year
2026: 3 · 2025: 1 · 2024: 3 · 2022: 1 · 2021: 1
FWCI
0.65
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
  • FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Deutsche Forschungsgemeinschaft
  • Fondazione Cariplo (2018-0511)
  • Research Campus Middle-Hessen
  • Philipps-Universität Marburg
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Kruppel-like factors research
Keywords
CAP2, MRTF-A, serum response factor, actin dynamics, actin turnover, G-actin, nuclear translocation, transcriptional coactivation, mouse embryonic fibroblasts, jasplakinolide, serum stimulation, heart development, skeletal muscle development
MeSH terms
Animals, Carrier Proteins, Cells, Cultured, Fibroblasts, Membrane Proteins, Trans-Activators, Serum Response Factor, Adaptor Proteins, Signal Transducing, Mice

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