Positive regulation of Itk PH domain function by soluble IP4.
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.
Huang
Yina H
YH
Department of Immunology, Scripps Research Institute, La Jolla, CA 92037, USA.
Grasis
Juris A
JA
Miller
Andrew T
AT
Xu
Ruo
R
Soonthornvacharin
Stephen
S
Andreotti
Amy H
AH
Tsoukas
Constantine D
CD
Cooke
Michael P
MP
Sauer
Karsten
K
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*
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