TY - JOUR TI - Non-canonical antagonism of PI3K by the kinase Itpkb delays thymocyte β-selection and renders it Notch-dependent AU - Westernberg, Luise AU - Conche, Claire AU - Huang, Yina Hsing AU - Rigaud, Stephanie AU - Deng, Yisong AU - Siegemund, Sabine AU - Mukherjee, Sayak AU - Nosaka, Lyn'Al AU - Das, Jayajit AU - Sauer, Karsten A2 - Rath, Satyajit VL - 5 PY - 2016 DA - 2016/02/11 SP - e10786 C1 - eLife 2016;5:e10786 DO - 10.7554/eLife.10786 UR - https://doi.org/10.7554/eLife.10786 AB - β-selection is the most pivotal event determining αβ T cell fate. Here, surface-expression of a pre-T cell receptor (pre-TCR) induces thymocyte metabolic activation, proliferation, survival and differentiation. Besides the pre-TCR, β-selection also requires co-stimulatory signals from Notch receptors - key cell fate determinants in eukaryotes. Here, we show that this Notch-dependence is established through antagonistic signaling by the pre-TCR/Notch effector, phosphoinositide 3-kinase (PI3K), and by inositol-trisphosphate 3-kinase B (Itpkb). Canonically, PI3K is counteracted by the lipid-phosphatases Pten and Inpp5d/SHIP-1. In contrast, Itpkb dampens pre-TCR induced PI3K/Akt signaling by producing IP4, a soluble antagonist of the Akt-activating PI3K-product PIP3. Itpkb-/- thymocytes are pre-TCR hyperresponsive, hyperactivate Akt, downstream mTOR and metabolism, undergo an accelerated β-selection and can develop to CD4+CD8+ cells without Notch. This is reversed by inhibition of Akt, mTOR or glucose metabolism. Thus, non-canonical PI3K-antagonism by Itpkb restricts pre-TCR induced metabolic activation to enforce coincidence-detection of pre-TCR expression and Notch-engagement. KW - PI3K KW - itpkb KW - notch KW - thymocytes KW - beta-selection KW - pre-TCR JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -