ZFIN ID: ZDB-PUB-170525-6
Redox modification of nuclear actin by MICAL-2 regulates SRF signaling.
Lundquist, M.R., Storaska, A.J., Liu, T.C., Larsen, S.D., Evans, T., Neubig, R.R., Jaffrey, S.R.
Date: 2014
Source: Cell   156(3): 563-76 (Journal)
Registered Authors: Evans, Todd
Keywords: none
MeSH Terms:
  • Actins/metabolism
  • Amino Acid Sequence
  • Anilides/pharmacology
  • Animals
  • Benzamides/pharmacology
  • Cell Line
  • Cell Nucleus/metabolism*
  • Cells, Cultured
  • DNA-Binding Proteins/metabolism
  • Gene Knockdown Techniques
  • Humans
  • Mice
  • Microfilament Proteins/analysis
  • Microfilament Proteins/genetics
  • Microfilament Proteins/metabolism*
  • Mixed Function Oxygenases/analysis
  • Mixed Function Oxygenases/genetics
  • Mixed Function Oxygenases/metabolism
  • Molecular Sequence Data
  • Nerve Growth Factor/metabolism
  • Neurites/metabolism
  • Oncogene Proteins, Fusion/metabolism
  • Oxidation-Reduction
  • Oxidoreductases/analysis
  • Oxidoreductases/genetics
  • Oxidoreductases/metabolism*
  • Rats
  • Sequence Alignment
  • Serum Response Factor/metabolism*
  • Signal Transduction*
  • Trans-Activators
  • Transcription, Genetic
  • Zebrafish
PubMed: 24440334 Full text @ Cell
FIGURES
ABSTRACT

The serum response factor (SRF) binds to coactivators, such as myocardin-related transcription factor-A (MRTF-A), and mediates gene transcription elicited by diverse signaling pathways. SRF/MRTF-A-dependent gene transcription is activated when nuclear MRTF-A levels increase, enabling the formation of transcriptionally active SRF/MRTF-A complexes. The level of nuclear MRTF-A is regulated by nuclear G-actin, which binds to MRTF-A and promotes its nuclear export. However, pathways that regulate nuclear actin levels are poorly understood. Here, we show that MICAL-2, an atypical actin-regulatory protein, mediates SRF/MRTF-A-dependent gene transcription elicited by nerve growth factor and serum. MICAL-2 induces redox-dependent depolymerization of nuclear actin, which decreases nuclear G-actin and increases MRTF-A in the nucleus. Furthermore, we show that MICAL-2 is a target of CCG-1423, a small molecule inhibitor of SRF/MRTF-A-dependent transcription that exhibits efficacy in various preclinical disease models. These data identify redox modification of nuclear actin as a regulatory switch that mediates SRF/MRTF-A-dependent gene transcription.

ADDITIONAL INFORMATION