Regulation of PP2A, PP4, and PP6 holoenzyme assembly by carboxyl-terminal methylation

Abstract The family of Phosphoprotein Phosphatases (PPPs) is responsible for most cellular serine and threonine dephosphorylation. PPPs achieve substrate specificity and selectivity by forming multimeric holoenzymes. PPP holoenzyme assembly is tightly controlled, and changes in the cellular repertoi...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Scott P. Lyons, Elora C. Greiner, Lauren E. Cressey, Mark E. Adamo, Arminja N. Kettenbach
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a61ca09668d84349ab1adb722ffb9903
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:a61ca09668d84349ab1adb722ffb9903
record_format	dspace
spelling	oai:doaj.org-article:a61ca09668d84349ab1adb722ffb99032021-12-05T12:15:09ZRegulation of PP2A, PP4, and PP6 holoenzyme assembly by carboxyl-terminal methylation10.1038/s41598-021-02456-z2045-2322https://doaj.org/article/a61ca09668d84349ab1adb722ffb99032021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-02456-zhttps://doaj.org/toc/2045-2322Abstract The family of Phosphoprotein Phosphatases (PPPs) is responsible for most cellular serine and threonine dephosphorylation. PPPs achieve substrate specificity and selectivity by forming multimeric holoenzymes. PPP holoenzyme assembly is tightly controlled, and changes in the cellular repertoire of PPPs are linked to human disease, including cancer and neurodegeneration. For PP2A, PP4, and PP6, holoenzyme formation is in part regulated by carboxyl (C)-terminal methyl-esterification (often referred to as “methylation”). Here, we use mass spectrometry-based proteomics, methylation-ablating mutations, and genome editing to elucidate the role of C-terminal methylation on PP2A, PP4, and PP6 holoenzyme assembly. We find that the catalytic subunits of PP2A, PP4, and PP6 are frequently methylated in cancer cells and that deletion of the C-terminal leucine faithfully recapitulates loss of methylation. We observe that loss of PP2A methylation consistently reduced B55, B56, and B72 regulatory subunit binding in cancer and non-transformed cell lines. However, Striatin subunit binding is only affected in non-transformed cells. For PP4, we find that PP4R1 and PP4R3β bind in a methylation-dependent manner. Intriguingly, loss of methylation does not affect PP6 holoenzymes. Our analyses demonstrate in an unbiased, comprehensive, and isoform-specific manner the crucial regulatory function of endogenous PPP methylation in transformed and non-transformed cell lines.Scott P. LyonsElora C. GreinerLauren E. CresseyMark E. AdamoArminja N. KettenbachNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Scott P. Lyons Elora C. Greiner Lauren E. Cressey Mark E. Adamo Arminja N. Kettenbach Regulation of PP2A, PP4, and PP6 holoenzyme assembly by carboxyl-terminal methylation
description	Abstract The family of Phosphoprotein Phosphatases (PPPs) is responsible for most cellular serine and threonine dephosphorylation. PPPs achieve substrate specificity and selectivity by forming multimeric holoenzymes. PPP holoenzyme assembly is tightly controlled, and changes in the cellular repertoire of PPPs are linked to human disease, including cancer and neurodegeneration. For PP2A, PP4, and PP6, holoenzyme formation is in part regulated by carboxyl (C)-terminal methyl-esterification (often referred to as “methylation”). Here, we use mass spectrometry-based proteomics, methylation-ablating mutations, and genome editing to elucidate the role of C-terminal methylation on PP2A, PP4, and PP6 holoenzyme assembly. We find that the catalytic subunits of PP2A, PP4, and PP6 are frequently methylated in cancer cells and that deletion of the C-terminal leucine faithfully recapitulates loss of methylation. We observe that loss of PP2A methylation consistently reduced B55, B56, and B72 regulatory subunit binding in cancer and non-transformed cell lines. However, Striatin subunit binding is only affected in non-transformed cells. For PP4, we find that PP4R1 and PP4R3β bind in a methylation-dependent manner. Intriguingly, loss of methylation does not affect PP6 holoenzymes. Our analyses demonstrate in an unbiased, comprehensive, and isoform-specific manner the crucial regulatory function of endogenous PPP methylation in transformed and non-transformed cell lines.
format	article
author	Scott P. Lyons Elora C. Greiner Lauren E. Cressey Mark E. Adamo Arminja N. Kettenbach
author_facet	Scott P. Lyons Elora C. Greiner Lauren E. Cressey Mark E. Adamo Arminja N. Kettenbach
author_sort	Scott P. Lyons
title	Regulation of PP2A, PP4, and PP6 holoenzyme assembly by carboxyl-terminal methylation
title_short	Regulation of PP2A, PP4, and PP6 holoenzyme assembly by carboxyl-terminal methylation
title_full	Regulation of PP2A, PP4, and PP6 holoenzyme assembly by carboxyl-terminal methylation
title_fullStr	Regulation of PP2A, PP4, and PP6 holoenzyme assembly by carboxyl-terminal methylation
title_full_unstemmed	Regulation of PP2A, PP4, and PP6 holoenzyme assembly by carboxyl-terminal methylation
title_sort	regulation of pp2a, pp4, and pp6 holoenzyme assembly by carboxyl-terminal methylation
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/a61ca09668d84349ab1adb722ffb9903
work_keys_str_mv	AT scottplyons regulationofpp2app4andpp6holoenzymeassemblybycarboxylterminalmethylation AT eloracgreiner regulationofpp2app4andpp6holoenzymeassemblybycarboxylterminalmethylation AT laurenecressey regulationofpp2app4andpp6holoenzymeassemblybycarboxylterminalmethylation AT markeadamo regulationofpp2app4andpp6holoenzymeassemblybycarboxylterminalmethylation AT arminjankettenbach regulationofpp2app4andpp6holoenzymeassemblybycarboxylterminalmethylation
_version_	1718372148900265984

Regulation of PP2A, PP4, and PP6 holoenzyme assembly by carboxyl-terminal methylation

Ejemplares similares