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Mutant actins that stabilise F-actin use distinct mechanisms to activate the SRF coactivator MAL

Guido Posern1, Francesc Miralles, Sebastian Guettler

  • 1Transcription Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, London, UK.

The EMBO Journal
|September 24, 2004
PubMed

Insights

Serum response factor coactivator MAL nuclear entry is regulated by G-actin. Specific actin mutants alter MAL interaction, influencing its nuclear localization through distinct mechanisms, with G15S acting directly.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Nuclear accumulation of serum response factor coactivator MAL/MKL1 is regulated by G-actin binding, retaining it in the cytoplasm under low Rho activity.
  • Previous studies identified actin mutants promoting MAL nuclear accumulation through an uncharacterized mechanism.

Purpose of the Study:

  • To investigate the direct interaction between actin mutants and MAL.
  • To elucidate the distinct mechanisms by which different actin mutants influence MAL nuclear localization.

Main Methods:

  • In vitro binding assays to assess actin-MAL interaction affinity.
  • Biochemical characterization of actin mutants (S14C, V159N, G15S) for binding properties with cofilin, ATP, and MAL.
  • Analysis of MAL nuclear accumulation in response to actin mutant expression, assessing dependence on Rho activity and actin treadmilling.

Main Results:

  • Actin directly interacts with MAL in vitro with high affinity.
  • Actin mutants G15S, S14C, and V159N stabilize F-actin.
  • MAL interaction is weakened with actin S14C and V159N, but strengthened with actin G15S.
  • MAL nuclear accumulation induced by actin S14C depends on Rho activity and actin treadmilling, whereas G15S-induced accumulation is independent of these factors.

Conclusions:

  • Actin G15S directly promotes MAL nuclear entry, independent of Rho activity and actin treadmilling.
  • Actin S14C and V159N modulate MAL nuclear entry through mechanisms dependent on Rho activity and actin dynamics.
  • These findings reveal distinct roles for actin-G-actin interactions in regulating MAL localization and serum response factor activity.

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