Selective Proteasomal Degradation of the B′β Subunit of Protein Phosphatase 2A by the E3 Ubiquitin Ligase Adaptor Kelch-like 15

Oberg, Elizabeth A.; Nifoussi, Shanna K.; Gingras, Anne‐Claude; Strack, Stefan

doi:10.1074/jbc.m112.420281

Cited by 39 publications

(51 citation statements)

References 47 publications

(54 reference statements)

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“…Based on our data and the study of Oberg et al 44. on KLHL15-dependent degradation of PP2A/B'-beta, we further hypothesize that the FRY tripeptide sequence may constitute a consensus KLHL15-Kelch domain interaction motif.…”

Section: Discussionsupporting

confidence: 77%

“…60). Along this line, KLHL15 mRNA levels were reported to be highest in lung, muscle and spleen, suggesting tissue-specific regulation of KLHL15 expression44. Interestingly, publicly available gene expression databases, such as MediSapiens, indicate highest KLHL15 expression levels predominantly in hematopoietic stem cells and in all four main types of leukemia (http://ist.medisapiens.com/#ENSG00000174010).…”

Section: Discussionmentioning

confidence: 97%

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Cullin3-KLHL15 ubiquitin ligase mediates CtIP protein turnover to fine-tune DNA-end resection

et al. 2016

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Human CtIP is a decisive factor in DNA double-strand break repair pathway choice by enabling DNA-end resection, the first step that differentiates homologous recombination (HR) from non-homologous end-joining (NHEJ). To coordinate appropriate and timely execution of DNA-end resection, CtIP function is tightly controlled by multiple protein–protein interactions and post-translational modifications. Here, we identify the Cullin3 E3 ligase substrate adaptor Kelch-like protein 15 (KLHL15) as a new interaction partner of CtIP and show that KLHL15 promotes CtIP protein turnover via the ubiquitin-proteasome pathway. A tripeptide motif (FRY) conserved across vertebrate CtIP proteins is essential for KLHL15-binding; its mutation blocks KLHL15-dependent CtIP ubiquitination and degradation. Consequently, DNA-end resection is strongly attenuated in cells overexpressing KLHL15 but amplified in cells either expressing a CtIP-FRY mutant or lacking KLHL15, thus impacting the balance between HR and NHEJ. Collectively, our findings underline the key importance and high complexity of CtIP modulation for genome integrity.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 97%

Cullin3-KLHL15 ubiquitin ligase mediates CtIP protein turnover to fine-tune DNA-end resection

et al. 2016

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“…Previous findings show that brain injury can result in a number of abnormalities in the biosynthesis, degradation, and post-translational modification of proteins which may have contributed to the effects of rmTBI on tau and PP2A/PR55 found here (Gao et al, 2006;Lee et al, 2013;Li et al, 2007;Oberg et al, 2012;Saatman et al, 2010;Sun et al, 2013;Yao et al, 2007). While further research is required to identify these mechanisms, given that the onset of the observed changes to PP2A/PR55 and htau occurred in the acute phase of mTBI it is possible that an early pathogenic event in the TBI injury cascade, such as excitotoxicity, neuroinflammation, hematoma, edema, or oxidative stress, may have initiated these effects (Blennow et al, 2012).…”

Section: Discussionmentioning

confidence: 83%

Sodium selenate, a protein phosphatase 2A activator, mitigates hyperphosphorylated tau and improves repeated mild traumatic brain injury outcomes

et al. 2016

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“…For example, phosphorylation of the N terminus of mammalian B9b by Clk2 promotes PP2A holoenzyme formation (Rodgers et al, 2011) but also destabilizes the isoform by promoting interaction with KLHL15/Cul3, leading to degradation (Oberg et al, 2012). The importance of localization is illustrated by the finding that B9a/B3, B9b/B4, B9h/B9, and B9g/B5 subunits can interact with either BZR1 or BRI1, depending on the ability of the B subunit to localize to the nucleus.…”

mentioning

confidence: 99%

Atypical Protein Phosphatase 2A Gene Families Do Not Expand via Paleopolyploidization

Booker

DeLong

2016

Plant Physiol.

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Protein phosphatase 2A (PP2A) presents unique opportunities for analyzing molecular mechanisms of functional divergence between gene family members. The canonical PP2A holoenzyme regulates multiple eukaryotic signaling pathways by dephosphorylating target proteins and contains a catalytic (C) subunit, a structural/scaffolding (A) subunit, and a regulatory (B) subunit. Genes encoding PP2A subunits have expanded into multigene families in both flowering plants and mammals, and the extent to which different isoform functions may overlap is not clearly understood. To gain insight into the diversification of PP2A subunits, we used phylogenetic analyses to reconstruct the evolutionary histories of PP2A gene families in Arabidopsis (Arabidopsis thaliana). Genes encoding PP2A subunits in mammals represent ancient lineages that expanded early in vertebrate evolution, while flowering plant PP2A subunit lineages evolved much more recently. Despite this temporal difference, our data indicate that the expansion of PP2A subunit gene families in both flowering plants and animals was driven by whole-genome duplications followed by nonrandom gene loss. Selection analysis suggests that the expansion of one B subunit gene family (B56/PPP2R5) was driven by functional diversification rather than by the maintenance of gene dosage. We also observed reduced expansion rates in three distinct B subunit subclades. One of these subclades plays a highly conserved role in cell division, while the distribution of a second subclade suggests a specialized function in supporting beneficial microbial associations. Thus, while whole-genome duplications have driven the expansion and diversification of most PP2A gene families, members of functionally specialized subclades quickly revert to singleton status after duplication events.

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Selective Proteasomal Degradation of the B′β Subunit of Protein Phosphatase 2A by the E3 Ubiquitin Ligase Adaptor Kelch-like 15

Cited by 39 publications

References 47 publications

Cullin3-KLHL15 ubiquitin ligase mediates CtIP protein turnover to fine-tune DNA-end resection

Cullin3-KLHL15 ubiquitin ligase mediates CtIP protein turnover to fine-tune DNA-end resection

Sodium selenate, a protein phosphatase 2A activator, mitigates hyperphosphorylated tau and improves repeated mild traumatic brain injury outcomes

Atypical Protein Phosphatase 2A Gene Families Do Not Expand via Paleopolyploidization

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