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

D. Yan, F. Li, M. L. Hall, C. Sage, W. H. Hu, Cosmas Giallourakis, G. Upadhyay, X. M. Ouyang, L. L. Du, John R Bethea, Z. Y. Chen, V. Yajnik, X. Z. Liu

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)755-764
Number of pages10
JournalJournal of molecular biology
Volume357
Issue number3
DOIs
StatePublished - Mar 31 2006

Keywords

  • Actin bundling protein
  • DOCK4
  • GTPase regulator
  • Harmonin

ASJC Scopus subject areas

  • Virology

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    Yan, D., Li, F., Hall, M. L., Sage, C., Hu, W. H., Giallourakis, C., Upadhyay, G., Ouyang, X. M., Du, L. L., Bethea, J. R., Chen, Z. Y., Yajnik, V., & Liu, X. Z. (2006). An isoform of GTPase regulator DOCK4 localizes to the stereocilia in the inner ear and binds to harmonin (USH1C). Journal of molecular biology, 357(3), 755-764. https://doi.org/10.1016/j.jmb.2006.01.017