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Cited by 85Protein Kinase Regulation and GTPase SignalingMicrotubule and mitosis dynamicsProtein Tyrosine Phosphatases

PP2A-B′ holoenzyme substrate recognition, regulation and role in cytokinesis

Open access
Wu, Cheng-Guo, Chen, Hui, Guo, Feng, Yadav, Vikash K, Mcilwain, Sean J, Rowse, Michael, Choudhary, Alka, Lin, Ziqing +13 more·2017·Cell Discovery
DOI 10.1038/celldisc.2017.27PMC PMC5586252
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Abstract

Protein phosphatase 2A (PP2A) is a major Ser/Thr phosphatase; it forms diverse heterotrimeric holoenzymes that counteract kinase actions. Using a peptidome that tiles the disordered regions of the human proteome, we identified proteins containing [LMFI]xx[ILV]xEx motifs that serve as interaction sites for B′-family PP2A regulatory subunits and holoenzymes. The B′-binding motifs have important roles in substrate recognition and in competitive inhibition of substrate binding. With more than 100 novel ligands identified, we confirmed that the recently identified LxxIxEx B′α-binding motifs serve as common binding sites for B′ subunits with minor variations, and that S/T phosphorylation or D/E residues at positions 2, 7, 8 and 9 of the motifs reinforce interactions. Hundreds of proteins in the human proteome harbor intrinsic or phosphorylation-responsive B′-interaction motifs, and localize at distinct cellular organelles, such as midbody, predicting kinase-facilitated recruitment of PP2A-B′ holoenzymes for tight spatiotemporal control of phosphorylation at mitosis and cytokinesis. Moroever, Polo-like kinase 1-mediated phosphorylation of Cyk4/RACGAP1, a centralspindlin component at the midbody, facilitates binding of both RhoA guanine nucleotide exchange factor (epithelial cell transforming sequence 2 (Ect2)) and PP2A-B′ that in turn dephosphorylates Cyk4 and disrupts Ect2 binding. This feedback signaling loop precisely controls RhoA activation and specifies a restricted region for cleavage furrow ingression. Our results provide a framework for further investigation of diverse signaling circuits formed by PP2A-B′ holoenzymes in various cellular processes.

AI snapshot

Written from the paper’s full text.

TL;DR

Using proteomic peptide phage display (ProP-PD) against PP2A B′-family subunits and holoenzymes, this study defines [LMFI]xx[ILV]xEx as a common B′-binding motif and identifies >100 new putative PP2A-B′ ligands. It further shows that Plk1 phosphorylation of Cyk4 recruits PP2A-B′ to the midbody, which then dephosphorylates Cyk4 and reverses Ect2 binding to control RhoA activation and cleavage furrow ingression.

Key findings

  • ProP-PD identified 23 B′α ligands and 72 B′γ1 ligands, with 14 overlapping; holoenzyme selections yielded 120 ligands for PP2A-B′γ1 and 94 for PP2A-B′ε. The consensus motif was [LMFI]xx[ILV]xEx, with negatively charged or phosphorylated residues at positions 2, 7, 8, and 9 enhancing binding.
  • More than 100 new B′ targets were identified, including 86 in intrinsically disordered regions not overlapping known/predicted domains. CIP2A’s motif peptide bound B′γ1 with an ITC affinity of 7.2 μm and competitively blocked PP2A-B′γ1 holoenzyme binding to GST-DENND2C or GST-SYT16.
  • Plk1 phosphorylation of Cyk4 increased B′ binding: nonphosphorylated Cyk4(1–177) barely bound GST-B′γ1 below 20 μm, whereas phosphorylated Cyk4 bound at concentrations as low as 0.6 μm, with half-maximal binding between 2.5 and 5 μm. Top-down MS identified phosphorylation at S149, S157, S164, and S170; the Cyk4 S149E peptide bound B′γ1 at 1.59 μm, 15-fold stronger than native peptide.
  • PP2A-B′ holoenzymes reversed the Plk1-generated pCyk4–Ect2 interaction. Knockdown of B′β/B′γ/B′ε trapped cells at little cleavage furrow ingression (12–15 μm diameter) with a diffused RhoA active zone (4–9 μm), compared with control cells showing cleavage furrow diameters <1–15 μm and RhoA zones <1–7 μm.

Methods

  • ProP-PD selections used a phage library tiling intrinsically disordered regions of the human proteome with 16-amino-acid peptides, against GST-tagged B′α and B′γ1 subunits and reconstituted PP2A-B′α, PP2A-B′γ1, and PP2A-B′ε holoenzymes; enriched pools were barcoded and analyzed by next-generation sequencing.
  • Binding was validated by GST pull-down, competitive binding assays, biolayer interferometry (BLI), isothermal titration calorimetry (ITC), gel filtration co-migration, and co-immunoprecipitation in mammalian cells.
  • Cyk4 phosphorylation was mapped by top-down MS with CID and ECD; cellular effects were examined by immunofluorescent staining of HeLa cells after siRNA knockdown of B′β/B′γ/B′ε and by Plk1 inhibitor BI-2536 treatment during anaphase.

Limitations

  • The paper states that BLI tends to overestimate binding affinities; measured BLI affinities were 0.03–11 μm, whereas ITC for the CIP2A peptide gave 7.2 μm.
  • The paper notes that ProP-PD is a competitive approach ideal for specificity rather than comprehensive ligand coverage, and it will not capture interactions that rely on post-translational modifications; free B′ subunits also tended to precipitate or aggregate, and selection against reconstituted PP2A-B′α failed to produce binders.
  • Not stated as a formal limitations section, but evident from the text: many bioinformatic motif predictions were not experimentally validated, and the knockdown experiments used simultaneous B′β/B′γ/B′ε siRNA rather than individual subunit depletion.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/celldisc.2017.27

Cites

65 of 65 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 20 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    A peptide of the KIAA1524-encoded protein CIP2A (713-FQHNRKLESVAEEHEI-722) is among the common peptides identified by ProP-PD for B′α, B′γ1 and B′ε subunits and holoenzymes.

    “A peptide of the KIAA1524-encoded protein CIP2A (the cancerous inhibitor of PP2A), 713- FQHNRKLESVAEEHEI-722, is among the common peptides identified by ProP-PD for B′α, B′γ1 and B′ε subunits and holoenzymes (Figure 1; Supplementary Tables S1 and S2).”
    Quote in the paperSubstantial claim
  • Findingown data

    PP2Ac, the scaffold A-subunit and B′γ1 regulatory subunits were found to be all localized at the dark zone and bulge region of the midbody, similar to Cyk4 itself, in HeLa cells.

    “Consistent with the biochemical observations, PP2Ac, the scaffold A-subunit and B′γ1 regulatory subunits were found to be all localized at the dark zone and bulge region of the midbody, similar to Cyk4 itself, in HeLa cells (Figure 5a).”
    Quote in the paperSubstantial claim
  • Findingown data

    The synthetic peptide NRKLESVAEEHE, representing the motif from CIP2A, blocks binding of PP2A-B′γ1 holoenzyme to GST-DENND2C or GST-SYT16 in a concentration-dependent manner.

    “the synthetic peptide NRKLESVAEEHE, representing the motif from CIP2A, blocks binding of PP2A-B′γ1 holoenzyme to GST-DENND2C or GST-SYT16 in a concentration-dependent manner (Figure 3b).”
    Quote in the paperSubstantial claim
  • Findingown data

    ProP-PD selections using B′α and B′γ1 as baits identified consensus binding motifs Lxx[IVL]xE for B′α and [LM]xx[ILV]xE for B′γ1.

    “established consensus motifs for binding (Figure 1a) of remaining peptides using the SLiMFinder algorithm [16] to Lxx[IVL]xE for B′α and [LM]xx[ILV]xE for B′γ1.”
    Quote in the paperSubstantial claim
  • Findingown data

    Plk1 inhibitor BI-2536, when applied to synchronized HeLa cells at anaphase, blocked and delayed the interaction between PP2Ac and Cyk4 in the presence of recombinant expression of V5-CIP2A during anaphase.

    “To further support that Plk1-mediated phosphorylation is crucial for Cyk4–PP2A interaction, we showed that Plk1 inhibitor BI-2536, when applied to synchronized Hela cells at anaphase, blocked and delayed the interaction between PP2Ac and Cyk4 in the presence of recombinant expression of V5-CIP2A during anaphase (Figure 5b).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The Plk1 inhibitor BI-2536 specifically inhibits Plk1 in the anaphase HeLa cell assay.
  • May combine two claims. 24
  • Classified as probably not a substantial claim. 4

  • May combine two claims.

    Findingown data

    The consensus motifs are [LMFI]xx[IVL]xE for PP2A-B′γ1 holoenzymes and [LM]xx[ILV]xE for PP2A-B′ε holoenzymes.

    “We established the consensus motifs [LMFI]xx[IVL]xE for PP2A-B′γ1 holoenzymes and [LM]xx[ILV]xE for PP2A-B′ε holoenzymes (Figure 1a)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Upon phosphorylation by Plk1, a Cyk4 construct (residue 1-177) containing the coiled-coil domain and a portion of the disordered region binds readily to B′ε, but not to PR70, a B′ family PP2A regulatory subunit.

    “Upon phosphorylation by Plk1, a Cyk4 construct (residue 1–177) containing the coiled-coil domain and a portion of the disordered region binds readily to B′ε, but not to PR70, a B′ family of PP2A regulatory subunit (Figure 4b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Many proteins at centrosome and midbody harbor intrinsic B′-interaction motifs; among the 10 proteins listed in Table 1, 6 were identified by ProP-PD.

    “Many proteins at centrosome and midbody harbor intrinsic B′-interaction motifs with some important examples shown in Table 1; among the 10 proteins listed, 6 was identified by ProP-PD (Supplementary Tables S1 and S2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Co-immunoprecipitation detected interactions of YFP-B′γ1 with CIP2A, SENP6 and USP53, but not with GLI2.

    “Consistently, we could detect the interactions of YFP-B′γ1 with CIP2A, SENP6 and USP53, but not with GLI2 by co-immunoprecipitation (Figure 2c).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    ProP-PD identified 23 peptide binders for B′α and 72 peptide binders for B′γ1, with an overlap of 14 peptides between the two sets.

    “After this analysis, 23 peptides were identified as binders for B′α and 72 peptides for B′γ1, with an overlap of 14 peptides between the two sets.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Phage selections against reconstituted PP2A-B′γ1 holoenzyme yielded 120 ligands and against PP2A-B′ε holoenzyme yielded 94 peptides.

    “However, we successfully obtained 120 ligands for PP2A-B′γ1 holoenzyme and 94 peptides for PP2A-B′ε holoenzyme (Figure 1b; Supplementary Table S2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both B′γ1 and B′ε co-migrate with phosphorylated Cyk4 (pCyk4; 1-177) over gel filtration chromatography, but not with non-phosphorylated Cyk4 (1-177).

    “Both B′γ1 and B′ε co-migrate with phosphorylated Cyk4 (pCyk4; 1–177) over gel filtration chromatography, but not non-phosphorylated Cyk4 (1–177; Figure 4c; Supplementary Figure S6).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    BLI-measured affinities between B′ subunits/holoenzyme and GST-tagged peptides are in the range 0.03-11 μM, around one order of magnitude higher than published isothermal titration calorimetry data, likely because BLI tends to overestimate binding affinity.

    “The results suggest that the affinities are in the range of 0.03–11 μm, which is around one order of magnitude higher than the published isothermal titration calorimetry data [12], likely because BLI tends to overestimate the binding affinity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Hertz EP, Kruse T, Davey NE et al. A conserved motif provides binding specificity to the PP2A-B56 phosphatase. Mol Cell 2016; 63: 686–695. source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    All tested ligands interact with PP2A-B′γ1 as well as PP2A-B′α holoenzymes, except AP2A1, which binds weakly to PP2A-B′γ1 and barely interacts with PP2A-B′α.

    “We expressed the selected peptides fused to GST and tested their interactions by GST pull down, showing that all tested ligands interact with PP2A-B′γ1 as well as PP2A-B′α holoenzymes, except AP2A1, which binds weakly to PP2A-B′γ1 and barely interacts with PP2A-B′α (Figure 2a).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Knockdown of B′β/B′γ/B′ε did not affect the distance between separating chromosomes but distinctly changed the diameters of cleavage furrow and the size of RhoA active zone compared to control.

    “While the distance between separating chromosomes for cells with B′β/B′γ/B′ε siRNAs was similar to the cells with control siRNA, the diameters of cleavage furrow and the size of RhoA active zone were distinctly different between control and B′β/B′γ/B′ε knockdown cells (Figure 5d).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Hundreds of proteins were identified to harbor B′-binding motifs, with 1-4 D/E residues at positions 2/7/8/9 that might partially correlate with binding affinity.

    “Hundreds of proteins were identified to harbor B′-binding motifs, with 1–4 D/E residues at position 2/7/8/9 that might partially correlate with the binding affinity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The phosphorylation-responsive B′-interaction motif of Cyk4 (143-LSTIDESGS-151) predicted by bioinformatic search is located upstream of the Ect2-binding site, which harbors several potential Plk1 phosphorylation sites.

    “The phosphorylation-responsive B′-interaction motif of Cyk4 (143-LSTIDESGS-151) predicted by bioinformatic search (Table 2) is located upstream of the Ect2-binding site, which harbors several potential Plk1 phosphorylation sites (Figure 4a).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    After treatment by PP2A-B′ holoenzymes, the pCyk4-Ect2 complex assembled after Plk1 phosphorylation failed to be pulled down together via GST-Cyk4 or co-migrate as a complex over gel filtration chromatography, suggesting that PP2A-B′ holoenzymes would reverse Cyk4-Ect2 interactions.

    “After treatment by PP2A-B′ holoenzymes, the pCyk4–Ect2 complex assembled after Plk1 phosphorylation failed to be pulled down together via GST-Cyk4 or co-migrate as a complex over gel filtration chromatography (Figure 5c), suggesting that PP2A-B′ holoenzymes would reverse Cyk4–Ect2 interactions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The binding affinity between B′γ1 and Cyk4 S149E peptide was measured to be 1.59 μM, 15-fold stronger than the native Cyk4 peptide and almost comparable to the peptide with double mutation S149E/S151E.

    “To corroborate with this notion, the binding affinity between B′γ1 and Cyk4 S149E peptide was measured to be 1.59 μm, 15-fold stronger than the native Cyk4 peptide and almost comparable to the peptide with double mutation S149E/S151E (Figure 4f).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    High-resolution top-down MS analysis revealed that Cyk4 is presented as mono-, bis-, tris-, tetrakis- and pentakis-phosphorylated proteoforms, and no unphosphorylated Cyk4 is detected.

    “High-resolution top-down MS analysis [39, 40] revealed that Cyk4 is presented as mono-, bis-, tris-, tetrakis- and pentakis-phosphorylated proteoforms. No unphosphorylated CyK4 is detected (Figure 4e, left panel).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [39] Peng Y, Gregorich ZR, Valeja SG et al. Top-down proteomics reveals concerted reductions in myofilament and Z-disc protein phosphorylation after acute myocardial infarction. Mol Cell Proteomics 2014; 13: 2752–2764. source

      Not checked in the free run.

    • cites [40] Ge Y, Rybakova IN, Xu Q, Moss RL . Top-down high-resolution mass spectrometry of cardiac myosin binding protein C revealed that truncation alters protein phosphorylation state. Proc Natl Acad Sci USA 2009; 106: 12658–12663. source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    In the merged set of B′ ligands, 126 new B′ targets were identified, among which 86 are in intrinsically disordered regions and not overlapping with any known/predicted domains.

    “In our merged set of B′ ligands, we identified 126 new B′ targets, among which 86 are in intrinsically disordered regions and not overlapping with any known/predicted domains.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Isothermal titration calorimetry measured an affinity of 7.2 μM between the CIP2A peptide and B′γ1, confirming that the affinities measured by BLI were overestimated.

    “We measured an affinity of 7.2 μm between the CIP2A peptide and B′γ1 by isothermal titration calorimetry (Figure 3c), which is comparable to the efficacy of CIP2A peptide in blocking holoenzyme–substrate interaction (Figure 3b), and confirms our earlier notion that the affinities measured by BLI (0.3 μm; Figure 2b) were overestimated.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    pS/T at position 6 cannot replace the consensus E residue; no interaction could be detected between B′γ1 and three phospho-peptides with pS/T at position 6.

    “Even with three negatively charged residues at positions 2, 7 and 8, no interaction could be detected between B′γ1 and these phospho-peptides (Supplementary Figure S2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Cells with B′β/B′γ/B′ε siRNAs were largely trapped at a stage with little ingression of cleavage furrow (12-15 μm in diameter) and diffused RhoA active zone (4-9 μm).

    “Cells with B′β/B′γ/B′ε siRNAs, however, were largely trapped at a stage with little ingression of cleavage furrow (12–15 μm in diameter), and diffused RhoA active zone (4–9 μm; Figure 5d).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Through this unbiased approach, we confirm that LxxIxEx is the preferred SLiM for interactions with different B′ regulatory subunits, and the specificity is highly similar between the isolated regulatory subunits and the holoenzymes.

    “Through this unbiased approach, we confirm that the LxxIxEx is the preferred SLiM for interactions with different B′ regulatory subunits, and we find that the specificity is highly similar between the isolated regulatory subunits and the holoenzymes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In addition to the LxxIxEx-containing ligands recently identified as B′α by AP-MS, we identified more than 100 new putative substrates or binding proteins for B′ family, suggesting that ProP-PD is a powerful approach for rapid identification of SLiMs for interaction with diverse PP2A holoenzymes.

    “In addition to the LxxIxEx-containing ligands recently identified as B′α by AP-MS [12], we identified more than 100 new putative substrates or binding proteins for B′ family, suggesting that ProP-PD is a powerful approach for rapid identification of SLiMs for interaction with diverse PP2A holoenzymes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Hertz EP, Kruse T, Davey NE et al. A conserved motif provides binding specificity to the PP2A-B56 phosphatase. Mol Cell 2016; 63: 686–695. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The minor differences between the binding affinities of the B′α and B′γ1 subunits support the notion that the B′ subunits have similar specificities, and that the partial overlap between the phage-derived ligands can be explained by minor differences in their interactions and the subsampling of a large set of available ligands.

    “The minor differences between the binding affinities of the B′α and B′γ1 subunits support the notion that the B′ subunits have similar specificities, and that the partial overlap between the phage-derived ligands can be explained by minor differences in their interactions and the subsampling of a large set of available ligands.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    These results suggest that PP2A-B′ holoenzymes are recruited by diverse centrosomal and midbody proteins, which might be highly responsive and enhanced by robust mitotic phosphorylation, presumably by Plk1 and other mitotic kinases.

    “These results suggest that PP2A-B′ holoenzymes are recruited by diverse centrosomal and midbody proteins, which might be highly responsive and enhanced by robust mitotic phosphorylation, presumably by Plk1 and other mitotic kinases.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Previous studies showed that phosphorylation or negatively charged residues at positions 2, 7, 8 and 9 enhance B′ binding.

    “Previous studies showed that phosphorylation or negatively charged residues at positions 2, 7, 8 and 9 enhance B′ binding [12, 17, 21].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [12] Hertz EP, Kruse T, Davey NE et al. A conserved motif provides binding specificity to the PP2A-B56 phosphatase. Mol Cell 2016; 63: 686–695. source

      Not checked in the free run.

    • cites [17] Kruse T, Zhang G, Larsen MS et al. Direct binding between BubR1 and B56-PP2A phosphatase complexes regulate mitotic progression. J Cell Sci 2013; 126 (Pt 5)): 1086–1092. source

      Not checked in the free run.

    • cites [21] Wang X, Bajaj R, Bollen M, Peti W, Page R . Expanding the PP2A interactome by defining a B56-specific SLiM. Structure 2016; 24: 2174–2181. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The co-immunoprecipitation experiments were repeated three times and representative results were shown.

    “The experiments were repeated three times and the representative results were shown.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Cyk4 is a phosphorylation-responsive substrate of PP2A-B′α.

    “It is important to mention that Cyk4 was also recently demonstrated to be a phosphorylation-responsive substrate of PP2A-B′α [12].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Hertz EP, Kruse T, Davey NE et al. A conserved motif provides binding specificity to the PP2A-B56 phosphatase. Mol Cell 2016; 63: 686–695. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    All experiments in the GST-mediated pull-down and competitive binding assays were repeated three times.

    “All experiments were repeated three times.”
    Quote in the paperNot a substantial claim
27 of 27

  • The authors state this as an assumption.

    Phosphorylation sites located closely downstream of the consensus B′-binding motif are not accessible to the active site of PP2A-B′ holoenzymes.

    “the upstream serine/threonine phosphorylation sites next to the motif can be readily placed to the active site of the PP2A-B′ holoenzyme, but not the downstream phosphorylation sites right next to the binding motif (Figure 1c).”
    “The later assumption might have exceptions, however.”

  • The paper relies on this without support.

    The Plk1 inhibitor BI-2536 specifically inhibits Plk1 in the anaphase HeLa cell assay.

    “Plk1 inhibitor BI-2536, when applied to synchronized Hela cells at anaphase, blocked and delayed the interaction between PP2Ac and Cyk4 in the presence of recombinant expression of V5-CIP2A during anaphase (Figure 5b).”

  • The paper relies on this without support.

    Failure of proper progression through cytokinesis often leads to polyploidy and aneuploidy and loss of genome integrity, a phenomenon closely associated with cancer.

    “Failure of proper progression through cytokinesis, such as those caused by B′ subunit knockdown (Figure 5), often lead to polyploidy and aneuploidy and loss of genome integrity, a phenomenon closely associated with cancer.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • B56 proteins recognize target proteins via a conserved binding pocket that binds LxxIxE consensus motifs.

    “The B56 proteins recognize their target proteins via a conserved binding pocket that binds to short linear motifs (SLIMs) with a LxxIxE consensus sequence in the target protein10,14–16.”

    From Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A (2023) · cites this paper as [16]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • PR70 assigned to two regulatory-subunit families

    Minor

    The Results describe PR70 as a B′-family subunit, whereas the Methods identify it as belonging to the B′′ family.

  • CIP2A peptide numbering does not span its sequence

    Minor

    The displayed CIP2A sequence contains 16 amino acids, but positions 713 through 722 span only 10 residues. Its stated endpoint is inconsistent with the sequence.

2 of 2

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Authors
Wu, C.-G., Chen, H., Guo, F., Yadav, V. K., Mcilwain, S. J., Rowse, M., Choudhary, A., Lin, Z., Li, Y., Gu, T., Zheng, A., Xu, Q., Lee, W., Resch, E., Johnson, B., Day, J., Ge, Y., Ong, I. M., Burkard, M. E., Ivarsson, Y., & Xing, Y.
Affiliations
  • University of Wisconsin–Madison (US)
  • Uppsala University (SE)
  • Fraunhofer Institute for Molecular Biology and Applied Ecology (DE)
Corresponding author
  • Ivarsson, Ylva
  • Xing, Yongna
ORCID
Venue
Cell Discovery
Publisher
Springer Science and Business Media LLC
Published
2017-08-08
Volume
3
Issue
1
Pages
17027-17027
ISSN
2056-5968 (ISSN-L)
DOI
10.1038/celldisc.2017.27
PMC
PMC5586252
OpenAlex
W2742664438
Semantic Scholar
13244ca57d7f3d2f5f49fdf3f8c483787bb64359
Cited by
85
References
65
Citations by year
2026: 3 · 2025: 7 · 2024: 11 · 2023: 7 · 2022: 11 · 2021: 15 · 2020: 16 · 2019: 8 · 2018: 5 · 2017: 2
FWCI
3.46
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Discovery (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • KTH Publication Database DiVA (KTH Royal Institute of Technology) (submittedVersion, other-oa)
  • Fraunhofer-Publica (Fraunhofer-Gesellschaft) (submittedVersion)
Funders
  • University of Wisconsin-Madison
  • Carl Tryggers Stiftelse för Vetenskaplig Forskning (CTS15:226)
  • Vetenskapsrådet (2016-04965, 2012-05092)
  • National Institutes of Health (NIH-R01, R01‐grant, 1s10od018475-01)
  • National Cancer Institute (T32CA157322, P30CA086862, P30CA014520)
  • National Institute of General Medical Sciences (R01GM117058, R01GM096060)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Keywords
protein phosphatase 2A, substrate recognition, protein-protein interaction motifs, phosphorylation-dependent binding, midbody, cytokinesis, PLK1, ECT2, RhoA activation, centralspindlin, cleavage furrow, peptidome, intrinsically disordered regions

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