Leucine Carboxyl Methyltransferase-1 Is Necessary for Normal Progression through Mitosis in Mammalian Cells

Lee, Jocelyn A.; Pallas, David C.

doi:10.1074/jbc.m704861200

Cited by 64 publications

(93 citation statements)

References 55 publications

(54 reference statements)

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“…2A), thereby stabilizing the pathway. Previous work suggests PME-1 regulates the association of B/55a subunits with the PP2A core dimer (16,17) and that reduced methylation of PP2A results in decreased B/55a-PP2A formation (44,45). Our data suggest that PME-1 may affect the activity of B/56-dependent PP2A in the regulation of ERK or that B/55a-PP2A may also regulate ERK dephosphorylation.…”

Section: Discussionmentioning

confidence: 48%

PME-1 Modulates Protein Phosphatase 2A Activity to Promote the Malignant Phenotype of Endometrial Cancer Cells

et al. 2014

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Protein phosphatase 2A (PP2A) negatively regulates tumorigenic signaling pathways, in part, by supporting the function of tumor suppressors like p53. The PP2A methylesterase PME-1 limits the activity of PP2A by demethylating its catalytic subunit. Here, we report the finding that PME-1 overexpression correlates with increased cell proliferation and invasive phenotypes in endometrial adenocarcinoma cells, where it helps maintain activated ERK and Akt by inhibiting PP2A. We obtained evidence that PME-1 could bind and regulate protein phosphatase 4 (PP4), a tumor-promoting protein, but not the related protein phosphatase 6 (PP6). When the PP2A, PP4, or PP6 catalytic subunits were overexpressed, inhibiting PME-1 was sufficient to limit cell proliferation. In clinical specimens of endometrial adenocarcinoma, PME-1 levels were increased and we found that PME-1 overexpression was sufficient to drive tumor growth in a xenograft model of the disease. Our findings identify PME-1 as a modifier of malignant development and suggest its candidacy as a diagnostic marker and as a therapeutic target in endometrial cancer. Cancer Res; 74(16); 4295-305. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 48%

PME-1 Modulates Protein Phosphatase 2A Activity to Promote the Malignant Phenotype of Endometrial Cancer Cells

et al. 2014

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“…Cell Culture and Transfection-Wild type, hemizygous, and homozygous LCMT-1 knock-out MEFs were prepared from E14.5 or older mouse embryo torsos from a previously described gene-trap LCMT-1 knock-out mouse (23) and then cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum, 1 mM sodium pyruvate, and nonessential amino acids at 37°C in 5% CO 2 . QBI293 (QBI-HEK-293 from QBiogene) cells were cultured in DMEM supplemented with 10% fetal bovine serum at 37°C in 10% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

“…1E (23). To examine whether this association is also compromised in MEFs isolated from LCMT-1 KO embryos and to quantitate the effect, B subunit/C subunit association was assayed by coimmunoprecipitation using cell lysates from LCMT-1 WT, hemizygous, and KO MEFs (Fig.…”

Section: Lcmt-1 Is the Major Methyltransferase For Pp4c And Pp6c-mentioning

confidence: 99%

“…A major function of PP2Ac carboxyl methylation is to regulate the formation of certain PP2Aheterotrimericforms,hereintermed"methylation-dependent PP2A heterotrimers" (16 -22). For example, PP2Ac methylation is required for efficient formation of heterotrimers containing the B family B-type subunits, B␣ (16,19,23), B␤ (24), and B␦, 4 but is not necessary for the formation of heterotrimers containing the BЉ or Bٞ subunits (19,24).…”

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confidence: 99%

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Leucine Carboxyl Methyltransferase 1 (LCMT-1) Methylates Protein Phosphatase 4 (PP4) and Protein Phosphatase 6 (PP6) and Differentially Regulates the Stable Formation of Different PP4 Holoenzymes

Hwang

Lee²,

Pallas

2016

Journal of Biological Chemistry

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The protein phosphatase 2A (PP2A) subfamily of phosphatases, PP2A, PP4, and PP6, are multifunctional serine/threonine protein phosphatases involved in many cellular processes. Carboxyl methylation of the PP2A catalytic subunit (PP2Ac) C-terminal leucine is regulated by the opposing activities of leucine carboxyl methyltransferase 1 (LCMT-1) and protein phosphatase methylesterase 1 (PME-1) and regulates PP2A holoenzyme formation. The site of methylation on PP2Ac is conserved in the catalytic subunits of PP4 and PP6, and PP4 is also methylated on that site, but the identities of the methyltransferase enzyme for PP4 are not known. Whether PP6 is methylated is also not known. Here we use antibodies specific for the unmethylated phosphatases to show that PP6 is carboxyl-methylated and that LCMT-1 is the major methyltransferase for PP2A, PP4, and PP6 in mouse embryonic fibroblasts (MEFs). Analysis of PP2A and PP4 complexes by blue native polyacrylamide gel electrophoresis (BN-PAGE) indicates that PP4 holoenzyme complexes, like those of PP2A, are differentially regulated by LCMT-1, with the PP4 regulatory subunit 1 (PP4R1)-containing PP4 complex being the most dramatically affected by the LCMT-1 loss. MEFs derived from LCMT-1 knock-out mouse embryos have reduced levels of PP2A B regulatory subunit and PP4R1 relative to control MEFs, indicating that LCMT-1 is important for maintaining normal levels of these subunits. Finally, LCMT-1 homozygous knock-out MEFs exhibited hyperphosphorylation of HDAC3, a reported target of the methylation-dependent PP4R1-PP4c complex. Collectively, our data suggest that LCMT-1 coordinately regulates the carboxyl methylation of PP2A-related phosphatases and, consequently, their holoenzyme assembly and function.

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“…However, a successful strategy based on this approach will likely require precise modulation of PME-1 or LCMT-1 activity. PP2A plays a number of critical functions in numerous cell types throughout the body (Janssens and Goris, 2001;Shi, 2009), and mice homozygous for a knock-out mutation of the murine PME-1 or LCMT-1 genes exhibit early postnatal or embryonic lethality respectively (Lee and Pallas, 2007;OrtegaGutierrez et al, 2008). Additionally, we observed that greater than 10 fold LCMT-1 over expression in second line of transgenic mice resulted in behavioral impairments on its own (data not shown).…”

Section: Discussionmentioning

confidence: 99%

The Role of PP2A Methylation in Susceptibility and Resistance to TBI and AD-Induced Neurodegeneration

Arancio¹,

Morrison²,

Nicholls³

et al. 2013

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) AND ADDRESS(ES) PERFORMING ORGANIZATION REPORT NUMBER Columbia UniversityNew York, NY 10032 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTThe focus of the current study is to test the effect of genetic manipulations that target the tau phosphatase, PP2A, on behavioral impairments resulting from shockwave exposure in a mouse model, and to compare those results with the effects of the same genetic manipulations on the sensitivity to AD-like impairments caused by acute beta-amyloid (Aβ) exposure. Our goal is to identify the molecular mechanisms that contribute to TBI or AD-related impairment so that this information can then be used to identify at-risk individuals and develop effective therapeutic approaches. The principal motivation behind this approach is the observation that aggregates of hyperphosphorylated tau are a common feature of multiple neurodegenerative conditions including Alzheimer's disease and traumatic brain injury-associated degeneration. We previously found that the two novel lines of transgenic mice will use in this study, altered sensitivity to Aβ-induced electrophysiological and behavioral impairments, and our hypothesis is that they will exert similar effects on shockwaveinduced impairments. This effort has required a substantial investment in developing equipment and testing protocols for exposing mice to a range of shockwave exposure conditions that mimic militarily relevant exposures and then assessing the biochemical and behavioral consequences of those exposures. There is currently a pressing need for mouse models and methodologies that reproduce the key features of blast exposure observed in humans, and the results of our experiments are a significant contribution to that effort. SUBJECT TERMS INTRODUCTION:Neurodegeneration resulting from both traumatic bra...

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Leucine Carboxyl Methyltransferase-1 Is Necessary for Normal Progression through Mitosis in Mammalian Cells

Cited by 64 publications

References 55 publications

PME-1 Modulates Protein Phosphatase 2A Activity to Promote the Malignant Phenotype of Endometrial Cancer Cells

PME-1 Modulates Protein Phosphatase 2A Activity to Promote the Malignant Phenotype of Endometrial Cancer Cells

Leucine Carboxyl Methyltransferase 1 (LCMT-1) Methylates Protein Phosphatase 4 (PP4) and Protein Phosphatase 6 (PP6) and Differentially Regulates the Stable Formation of Different PP4 Holoenzymes

The Role of PP2A Methylation in Susceptibility and Resistance to TBI and AD-Induced Neurodegeneration

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