title: Regulation of protein synthesis by IGF-I in proximal tubular epithelial cells.
abstract: Protein synthesis is required for renal hypertrophy, and proximal tubular epithelial cells are an important cell type involved in this process. We examined IGF-I regulation of protein synthesis in murine proximal tubular epithelial (MCT) cells. We focused on initial events in protein translation and the signaling events involved. Translation of capped mRNAs is under the control of eukaryotic initiation factor 4E (eIF4E). In the resting cell, eIF4E is normally kept in an inactive state by binding to 4E-BP1, its binding protein. Phosphorylation of 4E-BP1 results in dissociation of the eIF4E-4E-BP1 complex allowing eIF4E to initiate peptide synthesis. IGF-I stimulated protein synthesis, augmented phosphorylation of 4E-BP1 and promoted the dissociation of eIF4E from 4E-BP1. IGF-I stimulated the activities of phosphatidylinositol (PI) 3-kinase, Akt, and ERK1/2-type MAPK in MCT cells. IGF-I-induced phosphorylation of 4E-BP1, dissociation of the 4E-BP1-eIF4E complex, and increase in protein synthesis required activation of both PI 3-kinase and ERK pathways. Furthermore, ERK activation by IGF-I was also PI 3-kinase dependent. Transfection with the Thr37,46-->Ala37,46 mutant of 4E-BP1 showed that phosphorylation of Thr37,46 residues was required for IGF-I induction of protein synthesis in MCT cells. Our observations reveal the importance of initial events in protein translation in IGF-I-induced protein synthesis in MCT cells and identify the regulatory signaling pathways involved.
authors.affiliation: Division of Nephrology, Department of Medicine, University of Texas Health Science Center, South Texas Veterans Health Care System, Geriatrics Research and Education Center, San Antonio, Texas 78229-3900, USA.
authors.forename: Duraisamy
authors.initials: D
authors.lastname: Senthil
authors.forename: Goutam Ghosh
authors.initials: GG
authors.lastname: Choudhury
authors.forename: Hanna E
authors.initials: HE
authors.lastname: Abboud
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
authors.forename: Balakuntalam S
authors.initials: BS
authors.lastname: Kasinath
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D004790:Enzyme Induction / Q000502:physiology; D004847:Epithelial Cells / Q000378:metabolism; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D039642:Eukaryotic Initiation Factors; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000096:biosynthesis* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D013997:Time Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D039561:Eukaryotic Initiation Factor-4E; D039642:Eukaryotic Initiation Factors; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I; D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C499527:Eif4ebp1 protein, mouse; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse