An isoform of GTPase regulator DOCK4 localizes to the stereocilia in the inner ear and binds to harmonin (USH1C)

J Mol Biol. 2006 Mar 31;357(3):755-64. doi: 10.1016/j.jmb.2006.01.017. Epub 2006 Jan 23.


The driving forces for the regulation of cell morphology are the Rho family GTPases that coordinate the assembly of the actin cytoskeleton. This dynamic feature is a result of tight coupling between the cytoskeleton and signal transduction and is facilitated by actin-binding proteins (ABPs). Mutations in the actin bundling and PDZ domain-containing protein harmonin are the causes of Usher syndrome type 1C (USH1C), a syndrome of congenital deafness and progressive blindness, as well as certain forms of non-syndromic deafness. Here, we have used the yeast two-hybrid assay to isolate molecular partners of harmonin and identified DOCK4, an unconventional guanine exchange factor for the Rho family of guanosine triphosphatases (Rho GEF GTPases), as a protein interacting with harmonin. Detailed molecular analysis revealed that a novel DOCK4 isoform (DOCK4-Ex49) is expressed in the brain, eye and inner ear tissues. We have further provided evidence that the DOCK4-Ex49 binds to nucleotide free Rac as effectively as DOCK2 and DOCK4 and it is a potent Rac activator. By immunostaining using a peptide antibody specific to DOCK4-Ex49, we showed its localization in the inner ear within the hair bundles along the stereocilia (SC). Together, our data indicate a possible Rac-DOCK4-ABP harmonin-activated signaling pathway in regulating actin cytoskeleton organization in stereocilia.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Actins / metabolism
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Carrier Proteins / metabolism*
  • Cell Cycle Proteins
  • Cell Line
  • Cilia / enzymology
  • Cilia / metabolism
  • Cytoskeletal Proteins
  • Cytoskeleton / metabolism
  • Ear, Inner / enzymology
  • Ear, Inner / metabolism*
  • Exons
  • GTPase-Activating Proteins / immunology
  • GTPase-Activating Proteins / metabolism*
  • Guanine Nucleotide Exchange Factors / metabolism
  • Humans
  • Mice
  • Protein Isoforms / metabolism
  • Signal Transduction / physiology
  • Two-Hybrid System Techniques
  • rac GTP-Binding Proteins / metabolism
  • rho GTP-Binding Proteins / metabolism*


  • Actins
  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Cell Cycle Proteins
  • Cytoskeletal Proteins
  • DOCK4 protein, human
  • Dock4 protein, mouse
  • GTPase-Activating Proteins
  • Guanine Nucleotide Exchange Factors
  • Protein Isoforms
  • USH1C protein, human
  • Ush1c protein, mouse
  • rac GTP-Binding Proteins
  • rho GTP-Binding Proteins