Human SMG-1, a novel phosphatidylinositol 3-kinase-related protein kinase, associates with components of the mRNA surveillance complex and is involved in the regulation of nonsense-mediated mRNA decay.
Nonsense-mediated mRNA decay (NMD) is a conserved surveillance mechanism that eliminates imperfect mRNAs that contain premature translation termination codons (PTCs) and code for nonfunctional or potentially harmful polypeptides. We show that a novel phosphatidylinositol 3-kinase-related protein kinase, hSMG-1, is a human ortholog of a product of Caenorhabditis elegans smg-1, one of seven smg genes involved in NMD. hSMG-1 phosphorylates hUPF1/SMG-2 in vivo and in vitro at specific serine residues in SQ motifs. hSMG-1 can associate with hUPF1/SMG-2 and other components of the surveillance complex. In particular, overexpression of a kinase-deficient point mutant of hSMG-1, hSMG-1-DA, results in a marked suppression of the PTC-dependent beta-globin mRNA degradation; whereas that of wild-type hSMG-1 enhances it. We also show that inhibitors of hSMG-1 induce the accumulation of truncated p53 proteins in human cancer cell lines with p53 PTC mutation. Taken together, we conclude that hSMG-1 plays a critical role in NMD through the direct phosphorylation of hUPF1/SMG-2 in the evolutionally conserved mRNA surveillance complex.
Pubmed ID: 11544179 RIS Download
Amino Acid Sequence | Animals | Blotting, Northern | Caenorhabditis elegans | Cell Line | Cloning, Molecular | DNA, Complementary | Dose-Response Relationship, Drug | Globins | HeLa Cells | Humans | Metalloendopeptidases | Models, Genetic | Molecular Sequence Data | Multigene Family | Phosphatidylinositol 3-Kinases | Phosphorylation | Phylogeny | Plasmids | Precipitin Tests | Protein Binding | Protein Biosynthesis | Protein Isoforms | Protein Kinases | RNA, Messenger | Sequence Homology, Amino Acid | Time Factors | Transfection