Kinase-independent functions for Itk in TCR-induced regulation of Vav and the actin cytoskeleton

Derek Dombroski, Richard A. Houghtling, Christine M. Labno, Patricia Precht, Aya Takesono, Natasha J. Caplen, Daniel D. Billadeau, Ronald L. Wange, Janis K. Burkhardt, Pamela L. Schwartzberg

Research output: Contribution to journalArticle

97 Scopus citations

Abstract

The Tec family kinase Itk is an important regulator of Ca2+ mobilization and is required for in vivo responses to Th2-inducing agents. Recent data also implicate Itk in TCR-induced regulation of the actin cytoskeleton. We have evaluated the requirements for Itk function in TCR-induced actin polarization. Reduction of Itk expression via small interfering RNA treatment of the Jurkat human T lymphoma cell line or human peripheral blood T cells disrupted TCR-induced actin polarization, a defect that correlated with decreased recruitment of the Vav guanine nucleotide exchange factor to the site of Ag contact. Vav localization and actin polarization could be rescued by re-expression of either wild-type or kinase-inactive murine Itk but not by Itk containing mutations affecting the pleckstrin homology or Src homology 2 domains. Additionally, we find that Itk is constitutively associated with Vav. Loss of Itk expression did not alter gross patterns of Vav tyrosine phosphorylation but appeared to disrupt the interactions of Vav with SLP-76. Expression of membrane-targeted Vav, Vav-CAAX, can rescue the small interfering RNA to Itk-induced phenotype, implicating the alteration in Vav localization as directly contributing to the actin polarization defect. These data suggest a kinase-independent scaffolding function for Itk in the regulation of Vav localization and TCR-induced actin polarization.

Original languageEnglish (US)
Pages (from-to)1385-1392
Number of pages8
JournalJournal of Immunology
Volume174
Issue number3
DOIs
StatePublished - Feb 1 2005

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Dombroski, D., Houghtling, R. A., Labno, C. M., Precht, P., Takesono, A., Caplen, N. J., Billadeau, D. D., Wange, R. L., Burkhardt, J. K., & Schwartzberg, P. L. (2005). Kinase-independent functions for Itk in TCR-induced regulation of Vav and the actin cytoskeleton. Journal of Immunology, 174(3), 1385-1392. https://doi.org/10.4049/jimmunol.174.3.1385