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Published Online April 5, 2007
Science DOI: 10.1126/science.1138684

Reports

Submitted on December 11, 2006
Accepted on March 29, 2007

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 Sauer 1*

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, 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.
Karsten Sauer , E-mail: ksauer{at}scripps.edu

PH domain mediated protein recruitment to cellular membranes is of paramount importance for signal transduction. Recruitment of many PH domains is controlled through production and turnover of their membrane ligand Phosphatidylinositol(1,4,5)-trisphosphate. Here, we show that phosphorylation of the second messenger Inositol(1,4,5)trisphosphate into Inositol(1,3,4,5)tetrakisphosphate (IP4) establishes another mode of PH domain regulation through a soluble ligand. At physiological concentrations, IP4 promotes PH domain binding to Phosphatidylinositol(1,4,5)trisphosphate. This is required for full activation of the protein tyrosine kinase Itk after T cell receptor engagement. IP4 establishes a feedback loop of Phospholipase C{gamma}1 activation through Itk that is essential for T cell development.


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