Global loss of leucine carboxyl methyltransferase-1 causes severe defects in fetal liver hematopoiesis

Lee, Jocelyn A.; Wang, Zhengqi; Sambo, Danielle; Bunting, Kevin D.; Pallas, David C.

doi:10.1074/jbc.ra118.002012

Cited by 14 publications

(10 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It was already reported that deletion of LCMT-1 in mouse embryonic fibroblasts decreases methylation of PP2A C by >95%, methylation of PP4 C by ~93%, and methylation of PP6 C by ~87% (28). Furthermore, deletion of LCMT-1 in mammalian cells, or of its ortholog (PPM1) in yeast, reduces the formation of PP2A C/A/B heterotrimers, impairs catalytic activity, and reduces the steady-state abundance of the PP2A B, A, and C subunits (10)(11)(12)(13).…”

Section: D6 Methylation Sensitivity Is the Source Of A Detection Biamentioning

confidence: 99%

“…The major function of PP2A C carboxyl methylation is thought to be the stimulation of PP2A activity and the promotion of PP2A heterotrimeric complex assembly (8)(9)(10)(11)(12). For example, methylation is required for formation of B subunitcontaining heterotrimers in mammalian cells (13). Methylation similarly facilitates mammalian B′ (B56) and B″ (PR72) trimer assembly in cells, although it does not seem to be strictly required for complex assembly in vitro (14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Antibodies recognizing the C terminus of PP2A catalytic subunit are unsuitable for evaluating PP2A activity and holoenzyme composition

et al. 2020

View full text Add to dashboard Cite

The methyl-esterification of the C-terminal leucine of the protein phosphatase 2A (PP2A) catalytic (C) subunit is essential for the assembly of specific trimeric PP2A holoenzymes, and this region of the C subunit also contains two threonine and tyrosine phosphorylation sites. Most commercial antibodies—including the monoclonal antibody 1D6 that is part of a frequently used, commercial phosphatase assay kit—are directed toward the C terminus of the C subunit, raising questions as to their ability to recognize methylated and phosphorylated forms of the enzyme. Here, we tested several PP2A C antibodies, including monoclonal antibodies 1D6, 7A6, G-4, and 52F8 and the polyclonal antibody 2038 for their ability to specifically detect PP2A in its various modified forms, as well as to coprecipitate regulatory subunits. The tested antibodies preferentially recognized the nonmethylated form of the enzyme, and they did not coimmunoprecipitate trimeric holoenzymes containing the regulatory subunits B or B′, an issue that precludes their use to monitor PP2A holoenzyme activity. Furthermore, some of the antibodies also recognized the phosphatase PP4, demonstrating a lack of specificity for PP2A. Together, these findings suggest that reinterpretation of the data generated by using these reagents is required.

show abstract

Section: D6 Methylation Sensitivity Is the Source Of A Detection Biamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Antibodies recognizing the C terminus of PP2A catalytic subunit are unsuitable for evaluating PP2A activity and holoenzyme composition

et al. 2020

View full text Add to dashboard Cite

show abstract

“…PP2AC-LCMT interactions were verified in Leishmania by immunoprecipitation of the two coexpressing tagged versions of the proteins. In contrast to Leishmania , LCMT is essential in mice (44). Overexpression of LCMT produces SNF resistance (Table 1), but its inactivation produced even more resistance (Fig.…”

Section: Discussionmentioning

confidence: 99%

Genomewide Analysis of Mode of Action of the S -Adenosylmethionine Analogue Sinefungin in Leishmania infantum

Bhattacharya¹,

Sharma²,

Packianathan

et al. 2019

mSystems

View full text Add to dashboard Cite

The two main cellular metabolic one-carbon donors are reduced folates and S-adenosylmethionine, whose biosynthetic pathways have proven highly effective in chemotherapeutic interventions in various cell types. Sinefungin, a nucleoside analogue of S-adenosylmethionine, was shown to have potent activity against the protozoan parasite Leishmania. Here, we studied resistance to sinefungin using whole-genome approaches as a way to further our understanding of the role of S-adenosylmethionine in this parasite and to reveal novel potential drug targets. These approaches allowed the characterization of novel features related to S-adenosylmethionine function in Leishmania which could further help in the development of sinefungin-like compounds against this pathogenic parasite.

show abstract

“…For example, leucine carboxyl methyltransferase (LCMT-1)-mediated carboxyl methylation of PP4C is required for the formation of PP4-PP4R1 holoenzyme; and methylation of PP2A is required for the formation of PP2A holoenzyme containing Bα and Bβ-type regulatory subunits 34,35 . Loss of LCMT-1 reduces PP2A holoenzyme formation and causes severe defects in fetal hematopoiesis and, consequently, embryonic lethality in mice 36 . We speculate that the modification of a phosphatase regulatory subunit is more likely to regulate a more defined subset of substrates, thereby impacting specific signaling pathway(s).…”

Section: Discussionmentioning

confidence: 99%

A mitotic CDK5-PP4 phospho-signaling cascade primes 53BP1 for DNA repair in G1

Zheng¹,

Acharya²,

Choe³

et al. 2019

Nat Commun

View full text Add to dashboard Cite

Mitotic cells attenuate the DNA damage response (DDR) by phosphorylating 53BP1, a critical DDR mediator, to prevent its localization to damaged chromatin. Timely dephosphorylation of 53BP1 is critical for genome integrity, as premature recruitment of 53BP1 to DNA lesions impairs mitotic fidelity. Protein phosphatase 4 (PP4) dephosphorylates 53BP1 in late mitosis to allow its recruitment to DNA lesions in G1. How cells appropriately dephosphorylate 53BP1, thereby restoring DDR, is unclear. Here, we elucidate the underlying mechanism of kinetic control of 53BP1 dephosphorylation in mitosis. We demonstrate that CDK5, a kinase primarily functional in post-mitotic neurons, is active in late mitotic phases in non-neuronal cells and directly phosphorylates PP4R3β, the PP4 regulatory subunit that recognizes 53BP1. Specific inhibition of CDK5 in mitosis abrogates PP4R3β phosphorylation and abolishes its recognition and dephosphorylation of 53BP1, ultimately preventing the localization of 53BP1 to damaged chromatin. Our results establish CDK5 as a regulator of 53BP1 recruitment.

show abstract

Global loss of leucine carboxyl methyltransferase-1 causes severe defects in fetal liver hematopoiesis

Cited by 14 publications

References 56 publications

Antibodies recognizing the C terminus of PP2A catalytic subunit are unsuitable for evaluating PP2A activity and holoenzyme composition

Antibodies recognizing the C terminus of PP2A catalytic subunit are unsuitable for evaluating PP2A activity and holoenzyme composition

Genomewide Analysis of Mode of Action of the S -Adenosylmethionine Analogue Sinefungin in Leishmania infantum

A mitotic CDK5-PP4 phospho-signaling cascade primes 53BP1 for DNA repair in G1

Contact Info

Product

Resources

About