Phosphorylation of profilin by ROCK1 regulates polyglutamine aggregation

Mol Cell Biol. 2008 Sep;28(17):5196-208. doi: 10.1128/MCB.00079-08. Epub 2008 Jun 23.


Y-27632, an inhibitor of the Rho-associated kinase ROCK, is a therapeutic lead for Huntington disease (HD). The downstream targets that mediate its inhibitory effects on huntingtin (Htt) aggregation and toxicity are unknown. We have identified profilin, a small actin-binding factor that also interacts with Htt, as being a direct target of the ROCK1 isoform. The overexpression of profilin reduces the aggregation of polyglutamine-expanded Htt and androgen receptor (AR) peptides. This requires profilin's G-actin binding activity and its direct interaction with Htt, which are both inhibited by the ROCK1-mediated phosphorylation of profilin at Ser-137. Y-27632 blocks the phosphorylation of profilin in HEK293 cells and primary neurons, which maintains profilin in an active state. The knockdown of profilin blocks the inhibitory effect of Y-27632 on both AR and Htt aggregation. A signaling pathway from ROCK1 to profilin thus controls polyglutamine protein aggregation and is targeted by a promising therapeutic lead for HD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Amides / pharmacology
  • Animals
  • Cell Line
  • Chickens
  • Humans
  • Models, Biological
  • Nerve Tissue Proteins / metabolism
  • Neurons / drug effects
  • Neurons / pathology
  • Peptides / chemistry*
  • Peptides / metabolism*
  • Phosphorylation / drug effects
  • Phosphoserine / metabolism
  • Profilins / metabolism*
  • Protein Binding / drug effects
  • Protein Structure, Quaternary
  • Pyridines / pharmacology
  • Rats
  • Receptors, Androgen / metabolism
  • Signal Transduction / drug effects
  • rho GTP-Binding Proteins / metabolism
  • rho-Associated Kinases / metabolism*


  • Actins
  • Amides
  • Nerve Tissue Proteins
  • Peptides
  • Profilins
  • Pyridines
  • Receptors, Androgen
  • Y 27632
  • Phosphoserine
  • polyglutamine
  • rho-Associated Kinases
  • rho GTP-Binding Proteins