MNK2 inhibits eIF4G activation through a pathway involving serine-arginine-rich protein kinase in skeletal muscle.

Abstract

Skeletal muscle mass is regulated by activity, metabolism, and the availability of nutrients. During muscle atrophy, MNK2 expression increases. We found that MNK2 (mitogen-activated protein kinase-interacting kinase 2), but not MNK1, inhibited proteins involved in promoting protein synthesis, including eukaryotic translation initiation factor 4G (eIF4G) and mammalian target of rapamycin (mTOR). Phosphorylation at serine 1108 (Ser¹¹⁰⁸) of eIF4G, which is associated with enhanced protein translation, is promoted by insulin-like growth factor 1 and inhibited by rapamycin or starvation, suggesting that phosphorylation of this residue is regulated by mTOR. In cultured myotubes, small interfering RNA (siRNA) knockdown of MNK2 increased eIF4G Ser¹¹⁰⁸ phosphorylation and overcame rapamycin's inhibitory effect on this phosphorylation event. Phosphorylation of Ser¹¹⁰⁸ in eIF4G, in gastrocnemius muscle, was increased in mice lacking MNK2, but not those lacking MNK1, and this increased phosphorylation was maintained in MNK2-null animals under atrophy conditions and upon starvation. Conversely, overexpression of MNK2 decreased eIF4G Ser¹¹⁰⁸ phosphorylation. An siRNA screen revealed that serine-arginine-rich protein kinases linked increased MNK2 activity to decreased eIF4G phosphorylation. In addition, we found that MNK2 interacted with mTOR and inhibited phosphorylation of the mTOR target, the ribosomal kinase p70S6K (70-kD ribosomal protein S6 kinase), through a mechanism independent of the kinase activity of MNK2. These data indicate that MNK2 plays a unique role, not shared by its closest paralog MNK1, in limiting protein translation through its negative effect on eIF4G Ser¹¹⁰⁸ phosphorylation and p70S6K activation.

• Authors: Shou-Ih Hu, Mark Katz, Sherry Chin, Xiaoqing Qi, Joseph Cruz, Chikwendu Ibebunjo, Shanchuan Zhao, Amy Chen, David J Glass
• Journal: Science signaling (Sci Signal) Vol. 5 Issue 211 Pg. ra14 (Feb 14 2012) ISSN: 1937-9145 [Electronic] United States
• PMID: 22337810 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Eukaryotic Initiation Factor-4G
• Serine
• Insulin-Like Growth Factor I
• Dexamethasone
• Arginine
• Mknk1 protein, mouse
• Mknk2 protein, mouse
• Srpk1 protein, mouse
• Protein Serine-Threonine Kinases
• Ribosomal Protein S6 Kinases, 70-kDa
• TOR Serine-Threonine Kinases
• Sirolimus

Topics

• Animals
• Arginine (metabolism)
• Blotting, Western
• Cell Line
• Dexamethasone (toxicity)
• Eukaryotic Initiation Factor-4G (genetics, metabolism)
• Insulin-Like Growth Factor I (pharmacology)
• Mice
• Mice, Knockout
• Muscle, Skeletal (metabolism, pathology)
• Muscular Atrophy (etiology, genetics, metabolism)
• Myoblasts (drug effects, metabolism)
• Phosphorylation (drug effects)
• Protein Binding (drug effects)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• RNA Interference
• Ribosomal Protein S6 Kinases, 70-kDa (genetics, metabolism)
• Serine (genetics, metabolism)
• Signal Transduction
• Sirolimus (pharmacology)
• Starvation (complications)
• TOR Serine-Threonine Kinases (genetics, metabolism)