Identification of a novel amino acid response pathway triggering ATF2 phosphorylation in mammals.
It has been well established that amino acid availability can control gene expression. Previous studies have shown that amino acid depletion induces transcription of the ATF3 (activation transcription factor 3) gene through an amino acid response element (AARE) located in its promoter. This event requires phosphorylation of activating transcription factor 2 (ATF2), a constitutive AARE-bound factor. To identify the signaling cascade leading to phosphorylation of ATF2 in response to amino acid starvation, we used an individual gene knockdown approach by small interfering RNA transfection. We identified the mitogen-activated protein kinase (MAPK) module MEKK1/MKK7/JNK2 as the pathway responsible for ATF2 phosphorylation on the threonine 69 (Thr69) and Thr71 residues. Then, we progressed backwards up the signal transduction pathway and showed that the GTPase Rac1/Cdc42 and the protein Galpha12 control the MAPK module, ATF2 phosphorylation, and AARE-dependent transcription. Taken together, our data reveal a new signaling pathway activated by amino acid starvation leading to ATF2 phosphorylation and subsequently positively affecting the transcription of amino acid-regulated genes.
Chaveroux
Cédric
C
UMR 1019, Unité Nutrition Humaine, INRA de Theix, 63122 St. Genès Champanelle, France.
Jousse
Céline
C
Cherasse
Yoan
Y
Maurin
Anne-Catherine
AC
Parry
Laurent
L
Carraro
Valérie
V
Derijard
Benoit
B
Bruhat
Alain
A
Fafournoux
Pierre
P
D051698:Activating Transcription Factor 2 / Q000235:genetics / Q000378:metabolism*; D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000596:Amino Acids / Q000172:deficiency*; D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D048688:MAP Kinase Kinase 7 / Q000235:genetics / Q000378:metabolism; D048728:MAP Kinase Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011506:Proteins; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013217:Starvation / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D051698:Activating Transcription Factor 2; D051700:Activating Transcription Factor 3; D000596:Amino Acids; C497106:Atf2 protein, mouse; C497249:DDIT3 protein, human; D046912:Multiprotein Complexes; D011506:Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D051742:Transcription Factor CHOP; D048056:Mitogen-Activated Protein Kinase 9; C529271:EIF2AK4 protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D048728:MAP Kinase Kinase Kinase 1; D048688:MAP Kinase Kinase 7; C482569:MAP2K7 protein, human; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein