A role for p38 stress-activated protein kinase in regulation of cell growth via TORC1.
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.
Cully
Megan
M
Signal Transduction, Cancer Research UK London Research Institute, London WC2A 3PX, United Kingdom.
Genevet
Alice
A
Warne
Patricia
P
Treins
Caroline
C
Liu
Tao
T
Bastien
Julie
J
Baum
Buzz
B
Tapon
Nic
N
Leevers
Sally J
SJ
Downward
Julian
J
D000483:Alleles; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D048429:Cell Size / Q000187:drug effects; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000201:enzymology / Q000235:genetics; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007814:Larva / Q000235:genetics / Q000378:metabolism; D008297:Male; D009154:Mutation; D010053:Ovary / Q000166:cytology / Q000201:enzymology; D016877:Oxidants / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D034622:RNA Interference / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D013629:Tamoxifen / Q000494:pharmacology; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D004965:Estrogen Antagonists; D016877:Oxidants; D014157:Transcription Factors; C117726:gig protein, Drosophila; D013629:Tamoxifen; D006861:Hydrogen Peroxide; D048051:p38 Mitogen-Activated Protein Kinases; D020123:Sirolimus