Open Access Highly Accessed Research article

Cellular Notch responsiveness is defined by phosphoinositide 3-kinase-dependent signals

Grahame Mckenzie14*, George Ward1, Yvette Stallwood1, Emmanuel Briend1, Sofia Papadia2, Andrew Lennard1, Martin Turner3, Brian Champion1 and Giles E Hardingham2

Author affiliations

1 Lorantis Ltd., 410 Cambridge Science Park, Cambridge, CB4 0PE, UK

2 Centre for Neuroscience Research, University of Edinburgh, Summerhall, Edinburgh, EH9 1QH, UK

3 The Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge, CB2 4AT, UK

4 Inion Ltd, Unit 9B, Cambridge Science Park, Cambridge, CB4 0FG, UK

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Citation and License

BMC Cell Biology 2006, 7:10  doi:10.1186/1471-2121-7-10

Published: 28 February 2006



Notch plays a wide-ranging role in controlling cell fate, differentiation and development. The PI3K-Akt pathway is a similarly conserved signalling pathway which regulates processes such as differentiation, proliferation and survival. Mice with disrupted Notch and PI3K signalling show phenotypic similarities during haematopoietic cell development, suggesting functional interaction between these pathways.


We show that cellular responsiveness to Notch signals depends on the activity of the PI3K-Akt pathway in cells as diverse as CHO cells, primary T-cells and hippocampal neurons. Induction of the endogenous PI3K-Akt pathway in CHO cells (by the insulin pathway), in T-cells (via TCR activation) or in neurons (via TrKB activation) potentiates Notch-dependent responses. We propose that the PI3K-Akt pathway exerts its influence on Notch primarily via inhibition of GSK3-beta, a kinase known to phosphorylate and regulate Notch signals.


The PI3K-Akt pathway acts as a "gain control" for Notch signal responses. Since physiological levels of intracellular Notch are often low, coincidence with PI3K-activation may be crucial for induction of Notch-dependent responses.