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.
Highlights
Controlled protein phosphorylation and dephosphorylation is vital to effective cellular function in mammalian cells [1]
Lcmt12/2 animals display increased insulin resistance Because phosphatase 2A (PP2A) is involved in halting kinase cascades involved in growth and cell signaling [58], we looked at how a decrease in PP2A methylation would affect insulin signaling
We present a novel mouse model that is hypomorphic for LCMT1, the carboxyl-terminal protein methyltransferase that methylates PP2A, a major protein phosphatase
Summary
Controlled protein phosphorylation and dephosphorylation is vital to effective cellular function in mammalian cells [1]. Over one-third of the murine and human proteome is believed to be phosphorylated by the 540 murine (518 human) protein kinases at tyrosine, serine, and threonine residues [3,4,5]. These phosphorylation events overwhelmingly occur on serines and threonines with a ratio of approximately 1800:200:1 for pS:pT:pY modifications, respectively [6]. In contrast to the biological strategy evolved for the removal of tyrosine phosphorylation, the catalysis of phosphate removal from the thousands of substrates of the 428 human protein serine/threonine kinases is catalyzed by only ten protein serine/threonine phosphatases [9]. Unlike a typical tyrosine phosphatase, the major serine/threonine protein phosphatase (PP2A) recognizes a wide variety of substrates involved in many signaling cascades and cellular functions [10]
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