title: Functional interaction between RAFT1/FRAP/mTOR and protein kinase cdelta in the regulation of cap-dependent initiation of translation.
abstract: Hormones and growth factors induce protein translation in part by phosphorylation of the eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1). The rapamycin and FK506-binding protein (FKBP)-target 1 (RAFT1, also known as FRAP) is a mammalian homolog of the Saccharomyces cerevisiae target of rapamycin proteins (mTOR) that regulates 4E-BP1. However, the molecular mechanisms involved in growth factor-initiated phosphorylation of 4E-BP1 are not well understood. Here we demonstrate that protein kinase Cdelta (PKCdelta) associates with RAFT1 and that PKCdelta is required for the phosphorylation and inactivation of 4E-BP1. PKCdelta-mediated phosphorylation of 4E-BP1 is wortmannin resistant but rapamycin sensitive. As shown for serum, phosphorylation of 4E-BP1 by PKCdelta inhibits the interaction between 4E-BP1 and eIF4E and stimulates cap-dependent translation. Moreover, a dominant-negative mutant of PKCdelta inhibits serum-induced phosphorylation of 4E-BP1. These findings demonstrate that PKCdelta associates with RAFT1 and thereby regulates phosphorylation of 4E-BP1 and cap-dependent initiation of protein translation.
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: V
authors.initials: V
authors.lastname: Kumar
authors.forename: P
authors.initials: P
authors.lastname: Pandey
authors.forename: D
authors.initials: D
authors.lastname: Sabatini
authors.forename: M
authors.initials: M
authors.lastname: Kumar
authors.forename: P K
authors.initials: PK
authors.lastname: Majumder
authors.forename: A
authors.initials: A
authors.lastname: Bharti
authors.forename: G
authors.initials: G
authors.lastname: Carmichael
authors.forename: D
authors.initials: D
authors.lastname: Kufe
authors.forename: S
authors.initials: S
authors.lastname: Kharbanda
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D010448:Peptide Initiation Factors / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor); D014176:Protein Biosynthesis; D011493:Protein Kinase C / Q000235:genetics* / Q000378:metabolism; D051745:Protein Kinase C-delta; D012333:RNA, Messenger / Q000235:genetics; D020123:Sirolimus / Q000378:metabolism / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D000900:Anti-Bacterial Agents; D002352:Carrier Proteins; D007527:Isoenzymes; D010448:Peptide Initiation Factors; D010750:Phosphoproteins; D012333:RNA, Messenger; D017853:Phosphotransferases (Alcohol Group Acceptor); D058570:TOR Serine-Threonine Kinases; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D020123:Sirolimus; D000077191:Wortmannin