Glycogen synthase kinase 3beta is a negative regulator of growth factor-induced activation of the c-Jun N-terminal kinase.
The c-Jun N-terminal kinase (JNK)/stress activated protein kinase is preferentially activated by stress stimuli. Growth factors, particularly ligands for G protein-coupled receptors, usually induce only modest JNK activation, although they may trigger marked activation of the related extracellular signal-regulated kinase. In the present study, we demonstrated that homozygous disruption of glycogen synthase kinase 3beta (GSK-3beta) dramatically sensitized mouse embryonic fibroblasts (MEFs) to JNK activation induced by lysophosphatidic acid (LPA) and sphingosine-1-phosphate, two prototype ligands for G protein-coupled receptors. To a lesser degree, a lack of GSK-3beta also potentiated JNK activation in response to epidermal growth factor. In contrast, the absence of GSK-3beta decreased UV light-induced JNK activation. The increased JNK activation induced by LPA in GSK-3beta null MEFs was insufficient to trigger apoptotic cell death or growth inhibition. Instead, the increased JNK activation observed in GSK-3beta-/- MEFs was associated with an increased proliferative response to LPA, which was reduced by the inhibition of JNK. Ectopic expression of GSK-3beta in GSK-3beta-negative MEFs restrained LPA-triggered JNK phosphorylation and induced a concomitant decrease in the mitogenic response to LPA compatible with GSK-3beta through the inhibition of JNK activation, thus limiting LPA-induced cell proliferation. Mutation analysis indicated that GSK-3beta kinase activity was required for GSK-3beta to optimally inhibit LPA-stimulated JNK activation. Thus GSK-3beta serves as a physiological switch to specifically repress JNK activation in response to LPA, sphingosine-1-phosphate, or the epidermal growth factor. These results reveal a novel role for GSK-3beta in signal transduction and cellular responses to growth factors.
Liu
Shuying
S
Department of Molecular Therapeutics, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. sliu@mail.mdanderson.org
Yu
Shuangxing
S
Hasegawa
Yutaka
Y
Lapushin
Ruth
R
Xu
Hong-Ji
HJ
Woodgett
James R
JR
Mills
Gordon B
GB
Fang
Xianjun
X
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D004252:DNA Mutational Analysis; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005822:Genetic Vectors; D038362:Glycogen Synthase Kinase 3 / Q000737:chemistry / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006133:Growth Substances / Q000378:metabolism*; D006720:Homozygote; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008024:Ligands; D018021:Lithium Chloride / Q000494:pharmacology; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D011419:Propidium / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D013936:Thymidine / Q000737:chemistry; D013997:Time Factors; D014466:Ultraviolet Rays
D006133:Growth Substances; D008024:Ligands; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D011419:Propidium; D004815:Epidermal Growth Factor; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride; D013110:Sphingosine; C032881:lysophosphatidic acid; D013936:Thymidine