Non-canonical antagonism of PI3K by the kinase Itpkb delays thymocyte β-selection and renders it Notch-dependent
QH301-705.5
Cell Survival
Science
pre-TCR
beta-selection
PI3K
03 medical and health sciences
Animals
Biology (General)
Receptor, Notch1
Cell Proliferation
Phosphoinositide-3 Kinase Inhibitors
0303 health sciences
Thymocytes
Q
R
Cell Differentiation
Cell Biology
3. Good health
Mice, Inbred C57BL
Phosphotransferases (Alcohol Group Acceptor)
thymocytes
Medicine
itpkb
notch
DOI:
10.7554/elife.10786
Publication Date:
2016-02-11T18:45:15Z
AUTHORS (10)
ABSTRACT
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.
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CITATIONS (18)
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