TGFβ enforces activation of eukaryotic elongation factor-2 (eEF2) via inactivation of eEF2 kinase by p90 ribosomal S6 kinase (p90Rsk) to induce mesangial cell hypertrophy.
eEF2 phosphorylation is under tight control to maintain mRNA translation elongation. We report that TGFβ activates eEF2 by decreasing eEF2 phosphorylation and simultaneously increasing eEF2 kinase phosphorylation. Remarkably, inhibition of Erk1/2 blocked the TGFβ-induced dephosphorylation and phosphorylation of eEF2 and eEF2 kinase. TGFβ increased phosphorylation of p90Rsk in an Erk1/2-dependent manner. Inactive p90Rsk reversed TGFβ-inhibited phosphorylation of eEF2 and suppressed eEF2 kinase activity. Finally, inactive p90Rsk significantly attenuated TGFβ-induced protein synthesis and hypertrophy of mesangial cells. These results present the first evidence that TGFβ utilizes the two layered kinase module Erk/p90Rsk to activate eEF2 for increased protein synthesis during cellular hypertrophy.
Das
Falguni
F
Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA.
Ghosh-Choudhury
Nandini
N
Kasinath
Balakuntalam S
BS
Choudhury
Goutam Ghosh
GG
D000818:Animals; D049108:Cell Enlargement / Q000187:drug effects; D054736:Elongation Factor 2 Kinase / Q000037:antagonists & inhibitors*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D050527:Mesangial Cells / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D010456:Peptides, Cyclic; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D015852:Eukaryotic Initiation Factor-2; D010456:Peptides, Cyclic; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C473032:cyclic nonapeptide IP25; C517691:Eef2k protein, rat; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D054736:Elongation Factor 2 Kinase; D048049:Extracellular Signal-Regulated MAP Kinases