title: Positive regulation of Itk PH domain function by soluble IP4.
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-gamma1 activation through Itk that is essential for T cell development.
authors.affiliation: Department of Immunology, Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Yina H
authors.initials: YH
authors.lastname: Huang
authors.forename: Juris A
authors.initials: JA
authors.lastname: Grasis
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Miller
authors.forename: Ruo
authors.initials: R
authors.lastname: Xu
authors.forename: Stephen
authors.initials: S
authors.lastname: Soonthornvacharin
authors.forename: Amy H
authors.initials: AH
authors.lastname: Andreotti
authors.forename: Constantine D
authors.initials: CD
authors.lastname: Tsoukas
authors.forename: Michael P
authors.initials: MP
authors.lastname: Cooke
authors.forename: Karsten
authors.initials: K
authors.lastname: Sauer
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D020816:Amino Acid Motifs; D000818:Animals; D004075:Diglycerides / Q000378:metabolism; D025461:Feedback, Physiological; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism* / Q000494:pharmacology; D038041:Lymphopoiesis; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009924:Organ Culture Techniques; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015290:Second Messenger Systems; D015398:Signal Transduction; D012995:Solubility; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004075:Diglycerides; D007295:Inositol Phosphates; C491734:Lat protein, mouse; D008565:Membrane Proteins; D018129:Phosphatidylinositol Phosphates; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; C060974:phosphatidylinositol 3,4,5-triphosphate; C081655:inositol-1,3,4,5-tetrakisphosphate; D015544:Inositol 1,4,5-Trisphosphate; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase; D051966:Phospholipase C gamma