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.
Yamashita
A
A
Department of Molecular Biology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan.
Ohnishi
T
T
Kashima
I
I
Taya
Y
Y
Ohno
S
S
D000595:Amino Acid Sequence; D000818:Animals; D015152:Blotting, Northern; D017173:Caenorhabditis elegans; D002460:Cell Line; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005914:Globins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008666:Metalloendopeptidases; D008957:Models, Genetic; D008969:Molecular Sequence Data; D005810:Multigene Family; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry* / Q000235:genetics; D010766:Phosphorylation; D010802:Phylogeny; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D014176:Protein Biosynthesis; D020033:Protein Isoforms; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013997:Time Factors; D014162:Transfection
D018076:DNA, Complementary; D005914:Globins; D008666:Metalloendopeptidases; D019869:Phosphatidylinositol 3-Kinases; D020033:Protein Isoforms; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; C514704:SMG1 protein, human; C070738:O-sialoglycoprotein endopeptidase