A Role for p38 Stress-Activated Protein Kinase in Regulation of Cell Growth via TORC1

Author:

Cully Megan1,Genevet Alice2,Warne Patricia1,Treins Caroline1,Liu Tao3,Bastien Julie1,Baum Buzz3,Tapon Nic2,Leevers Sally J.4,Downward Julian1

Affiliation:

1. Signal Transduction

2. Apoptosis and Proliferation Control

3. MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom

4. Growth Control Laboratories, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom

Abstract

ABSTRACT The target of rapamycin (TOR) complex 1 (TORC1) signaling pathway is a critical regulator of translation and cell growth. To identify novel components of this pathway, we performed a kinome-wide RNA interference (RNAi) screen in Drosophila melanogaster S2 cells. RNAi targeting components of the p38 stress-activated kinase cascade prevented the cell size increase elicited by depletion of the TOR negative regulator TSC2. In mammalian and Drosophila tissue culture, as well as in Drosophila ovaries ex vivo , p38-activating stresses, such as H 2 O 2 and anisomycin, were able to activate TORC1. This stress-induced TORC1 activation could be blocked by RNAi against mitogen-activated protein kinase kinase 3 and 6 (MKK3/6) or by the overexpression of dominant negative Rags. Interestingly, p38 was also required for the activation of TORC1 in response to amino acids and growth factors. Genetic ablation either of p38b or licorne , its upstream kinase, resulted in small flies consisting of small cells. Mutants with mutations in licorne or p38b are nutrition sensitive; low-nutrient food accentuates the small-organism phenotypes, as well as the partial lethality of the p38b null allele. These data suggest that p38 is an important positive regulator of TORC1 in both mammalian and Drosophila systems in response to certain stresses and growth factors.

Publisher

American Society for Microbiology

Subject

Cell Biology,Molecular Biology

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