Arp5 Is a Key Regulator of Myocardin in Smooth Muscle Cells

J Cell Biol. 2014 Mar 3;204(5):683-96. doi: 10.1083/jcb.201307158. Epub 2014 Feb 24.

Abstract

Myocardin (Myocd) and Myocd-related transcription factors (MRTFs) are robust coactivators of serum response factor (SRF). RPEL motifs are monomeric globular actin (G-actin) binding elements that regulate MRTF localization and activity. However, the function of the RPEL motif in Myocd is largely unknown because of its low affinity for G-actin. Here, we demonstrated that the Myocd RPEL motif bound to actin-related protein 5 (Arp5) instead of conventional actin, resulting in a significant suppression of Myocd activity. In addition, Arp5 bound to a DNA binding domain of SRF via its C-terminal sequence and prevented the association of the Myocd-SRF complex with the promoter regions of smooth muscle genes. Well-differentiated smooth muscle cells mainly expressed a specific splicing variant of arp5; therefore, the protein level of Arp5 was markedly reduced by partial messenger RNA decay and translational suppression. In dedifferentiated smooth muscle cells, Arp5 knockdown restored the differentiated phenotype via Myocd activation. Thus, Arp5 is a key regulator of Myocd activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Amino Acid Motifs
  • Amino Acid Sequence
  • Angiopoietin-like Proteins
  • Angiopoietins / chemistry
  • Angiopoietins / metabolism
  • Angiopoietins / physiology*
  • Binding Sites
  • Cell Nucleus / metabolism
  • Gene Knockdown Techniques
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Molecular Sequence Data
  • Myocytes, Smooth Muscle / metabolism*
  • Nuclear Proteins / analysis
  • Nuclear Proteins / metabolism*
  • Phenotype
  • Protein Interaction Mapping
  • Protein Structure, Tertiary
  • Protein Transport
  • Sequence Alignment
  • Trans-Activators / analysis
  • Trans-Activators / metabolism*

Substances

  • ANGPTL6 protein, human
  • Angiopoietin-like Proteins
  • Angiopoietins
  • Nuclear Proteins
  • Trans-Activators
  • myocardin