title: Circumventing embryonic lethality with Lcmt1 deficiency: generation of hypomorphic Lcmt1 mice with reduced protein phosphatase 2A methyltransferase expression and defects in insulin signaling.
abstract: Protein phosphatase 2A (PP2A), the major serine/threonine phosphatase in eukaryotic cells, is a heterotrimeric protein composed of structural, catalytic, and targeting subunits. PP2A assembly is governed by a variety of mechanisms, one of which is carboxyl-terminal methylation of the catalytic subunit by the leucine carboxyl methyltransferase LCMT1. PP2A is nearly stoichiometrically methylated in the cytosol, and although some PP2A targeting subunits bind independently of methylation, this modification is required for the binding of others. To examine the role of this methylation reaction in mammalian tissues, we generated a mouse harboring a gene-trap cassette within intron 1 of Lcmt1. Due to splicing around the insertion, Lcmt1 transcript and LCMT1 protein levels were reduced but not eliminated. LCMT1 activity and methylation of PP2A were reduced in a coordinate fashion, suggesting that LCMT1 is the only PP2A methyltransferase. These mice exhibited an insulin-resistance phenotype, indicating a role for this methyltransferase in signaling in insulin-sensitive tissues. Tissues from these animals will be vital for the in vivo identification of methylation-sensitive substrates of PP2A and how they respond to differing physiological conditions.
authors.affiliation: Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Kennen B
authors.initials: KB
authors.lastname: MacKay
authors.forename: Yiping
authors.initials: Y
authors.lastname: Tu
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Young
authors.forename: Steven G
authors.initials: SG
authors.lastname: Clarke
mesh_terms: D000818:Animals; D015870:Gene Expression; D005804:Genes, Lethal; D005947:Glucose / Q000502:physiology; D006720:Homozygote; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D000078790:Insulin Secretion; D008297:Male; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016254:Mutagenesis, Insertional; D011497:Protein O-Methyltransferase / Q000172:deficiency / Q000235:genetics*; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction
chemical_list: D007328:Insulin; C586068:Lcmt1 protein, mouse; D011497:Protein O-Methyltransferase; D054648:Protein Phosphatase 2; D005947:Glucose