The splicing factor SF2/ASF regulates translation initiation by enhancing phosphorylation of 4E-BP1.
The SR protein SF2/ASF has been initially characterized as a splicing factor but has also been shown to mediate postsplicing activities such as mRNA export and translation. Here we demonstrate that SF2/ASF promotes translation initiation of bound mRNAs and that this activity requires the presence of the cytoplasmic cap-binding protein eIF4E. SF2/ASF promotes translation initiation by suppressing the activity of 4E-BP, a competitive inhibitor of cap-dependent translation. This activity is mediated by interactions of SF2/ASF with both mTOR and the phosphatase PP2A, two key regulators of 4E-BP phosphorylation. These findings suggest the model whereby SF2/ASF functions as an adaptor protein to recruit the signaling molecules responsible for regulation of cap-dependent translation of specific mRNAs. Taken together, these data suggest a novel mechanism for the activation of translation initiation of a subset of mRNAs bound by the shuttling protein SF2/ASF.
Michlewski
Gracjan
G
Medical Research Council Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
Sanford
Jeremy R
JR
Cáceres
Javier F
JF
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D020134:Catalytic Domain; D018797:Cell Cycle Proteins; D002457:Cell Extracts; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010442:Peptide Chain Initiation, Translational; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism; D012315:RNA Caps / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors; D058570:TOR Serine-Threonine Kinases
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D002457:Cell Extracts; C087000:EIF4EBP1 protein, human; D009687:Nuclear Proteins; D010750:Phosphoproteins; D012315:RNA Caps; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; D000068103:Serine-Arginine Splicing Factors; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C517189:PPP2CA protein, human; D054648:Protein Phosphatase 2