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


RESULTS
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.


CONCLUSIONS
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.
McKenzie
Grahame
G
Lorantis Ltd., Cambridge, CB4 0PE, UK. grahame.mckenzie@inion.com
Ward
George
G
Stallwood
Yvette
Y
Briend
Emmanuel
E
Papadia
Sofia
S
Lennard
Andrew
A
Turner
Martin
M
Champion
Brian
B
Hardingham
Giles E
GE
D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D018021:Lithium Chloride / Q000494:pharmacology; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051381:Rats; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects
D015704:CD4 Antigens; D051880:Receptors, Notch; D019869:Phosphatidylinositol 3-Kinases; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride