TI - MNK2 inhibits eIF4G activation through a pathway involving serine-arginine-rich protein kinase in skeletal muscle . AB - 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 (Ser(1) (1) (0) (8)) 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 Ser(1) (1) (0) (8) phosphorylation and overcame rapamycin's inhibitory effect on this phosphorylation event . Phosphorylation of Ser(1) (1) (0) (8) 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 Ser(1) (1) (0) (8) 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 Ser(1) (1) (0) (8) phosphorylation and p70S6K activation .