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Science 316 (5826): 886-889

Copyright © 2007 by the American Association for the Advancement of Science

Positive Regulation of Itk PH Domain Function by Soluble IP4

Yina H. Huang,1 Juris A. Grasis,2 Andrew T. Miller,3 Ruo Xu,4 Stephen Soonthornvacharin,3 Amy H. Andreotti,4 Constantine D. Tsoukas,2 Michael P. Cooke,3 Karsten Sauer1*

Abstract: Pleckstrin homology (PH) domain–mediated protein recruitment to cellular membranes is of paramount importance for signal transduction. The recruitment of many PH domains is controlled through production and turnover of their membrane ligand, phosphatidylinositol 3,4,5-trisphosphate (PIP3). We show that phosphorylation of the second messenger inositol 1,4,5-trisphosphate (IP3) into inositol 1,3,4,5-tetrakisphosphate (IP4) establishes another mode of PH domain regulation through a soluble ligand. At physiological concentrations, IP4 promoted PH domain binding to PIP3. In primary mouse CD4+CD8+ thymocytes, this was required for full activation of the protein tyrosine kinase Itk after T cell receptor engagement. Our data suggest that IP4 establishes a feedback loop of phospholipase C–{gamma}1 activation through Itk that is essential for T cell development.

1 Department of Immunology, Scripps Research Institute, La Jolla, CA 92037, USA.
2 Department of Biology and Center for Microbial Studies, San Diego State University, San Diego, CA 92182, USA.
3 Genomics Institute of the Novartis Research Foundation (GNF), San Diego, CA 92121, USA.
4 Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA 50011, USA.

* To whom correspondence should be addressed. E-mail: ksauer{at}scripps.edu

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Science Signaling. ISSN 1937-9145 (pre-2008: Science's STKE. ISSN 1525-8882)