Identification of Methylation‐Dependent Protein Phosphatase 2A Activity Correlated with Changes in Insulin Secretion and Glucose Tolerance in Mice with Hypomorphic Expression of the LCMT1 Protein Carboxyl Methyltransferase

Protein Phosphatase 2 A (PP2A) is a highly conserved, broad specificity, heterotrimeric serine/threonine phosphatase involved in nearly all cytosolic processes. PP2A control is manifested through subunit composition, small molecule and peptide inhibitors as well as post‐translational modifications. One such modification, methylation of the C‐terminal leucine by LCMT1, regulates PP2A subunit assembly, specifically Bα subunit binding, and thus substrate specificity. In this study we generate a mouse homozygous for an Lcmt1 gene‐trap cassette, yet expressing reduced Lcmt1 transcript and protein. Full length Lcmt1 transcript is achieved through alternative splicing around the genetrap cassette in a tissue specific manner. Reduced LCMT1 correlates with a concomitant reduction of PP2A methylation and an increase in PP2A demethylation confirming LCMT1 as the main PP2A methyltransferase. Lcmt1 homozygous gene‐trapped mice were born in a non‐mendelian ratio suggesting embryonic lethality. Adult Lcmt1 hypomorphic animals display decreased glucose tolerance and increased glucose‐stimulated insulin secretion suggesting an insulin resistance phenotype. Our results indicate that PP2A methylation has a role in propagation of the insulin‐signaling cascade, possibly through altered subunit composition of PP2A. This work was supported by the National Institutes of Health (GM026020)