Controlling Ser/Thr protein phosphatase PP1 activity and function through interaction with regulatory subunits

Casamayor, Antonio; Ariño, Joaquı́n

doi:10.1016/bs.apcsb.2020.06.004

Cited by 29 publications

(22 citation statements)

References 230 publications

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“…Among these proteins, due to the fact of their pleiotropic roles in the dynamic regulation of protein function and cellular distribution, enzymes involved in dephosphorylation processes and, in particular protein phosphatase 1 (PP1), are of interest. PP1 is among the most active drivers of protein dephosphorylation [2]. In humans, there are three PP1 catalytic (PP1c) isoforms expressed by three distinct genes [3]; however, Plasmodium spp.…”

Section: Introductionmentioning

confidence: 99%

“…Hence, it is reasonable to expect that acting on PP1c interactions or interactors in Plasmodium may lead to the development of selective drugs. In yeast and mammals, PP1c has been shown to function almost exclusively in complexes [7][8][9][10] with diverse regulators/partners to dephosphorylate a plethora of proteins involved in many cellular processes including glycogen metabolism, transcription or mitosis [2]. So far, hundreds of partners have been reported, and many of them have been shown to be involved in the coordination of PP1c activities.…”

Section: Introductionmentioning

confidence: 99%

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Mapping PP1c and Its Inhibitor 2 Interactomes Reveals Conserved and Specific Networks in Asexual and Sexual Stages of Plasmodium

Witte

Aliouat

Chhuon

et al. 2022

IJMS

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Malaria parasites require multiple phosphorylation and dephosphorylation steps to drive signaling pathways for proper differentiation and transformation. Several protein phosphatases, including protein phosphatase 1 (PP1), one of the main dephosphorylation enzymes, have been shown to be indispensable for the Plasmodium life cycle. The catalytic subunit of PP1 (PP1c) participates in cellular processes via dynamic interactions with a vast number of binding partners that contribute to its diversity of action. In this study, we used Plasmodium berghei transgenic parasite strains stably expressing PP1c or its inhibitor 2 (I2) tagged with mCherry, combined with the mCherry affinity pulldown of proteins from asexual and sexual stages, followed by mass spectrometry analyses. Mapped proteins were used to identify interactomes and to cluster functionally related proteins. Our findings confirm previously known physical interactions of PP1c and reveal enrichment of common biological processes linked to cellular component assembly in both schizonts and gametocytes to biosynthetic processes/translation in schizonts and to protein transport exclusively in gametocytes. Further, our analysis of PP1c and I2 interactomes revealed that nuclear export mediator factor and peptidyl-prolyl cis-trans isomerase, suggested to be essential in P. falciparum, could be potential targets of the complex PP1c/I2 in both asexual and sexual stages. Our study emphasizes the adaptability of Plasmodium PP1 and provides a fundamental study of the protein interaction landscapes involved in a myriad of events in Plasmodium, suggesting why it is crucial to the parasite and a source for alternative therapeutic strategies.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mapping PP1c and Its Inhibitor 2 Interactomes Reveals Conserved and Specific Networks in Asexual and Sexual Stages of Plasmodium

Witte

Aliouat

Chhuon

et al. 2022

IJMS

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“…Previous studies revealed that the RVXF motif and T73 phosphorylation were required for PPP1R14C to bind and inhibit PP1, respectively 34–36 (Figure 5D). IP assays using antibodies against PPP1R14C demonstrated that p‐PPP1R14C/PP1/p‐GSK3β‐Ser9 formed a complex in TNBC cells (Figure 5E).…”

Section: Resultsmentioning

confidence: 78%

“…Studies have indicated that PPP1R14C regulates the protein activity depending on its inhibitory effect on PP1, and thus modulates the biological activities of numerous key proteins 20,27,34 . Dedinszki et al.…”

Section: Discussionmentioning

confidence: 99%

Protein phosphatase 1 regulatory inhibitor subunit 14C promotes triple‐negative breast cancer progression via sustaining inactive glycogen synthase kinase 3 beta

Jian

Kong

et al. 2022

Clinical & Translational Med

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Triple‐negative breast cancer (TNBC) is fast‐growing and highly metastatic with the poorest prognosis among the breast cancer subtypes. Inactivation of glycogen synthase kinase 3 beta (GSK3β) plays a vital role in the aggressiveness of TNBC; however, the underlying mechanism for sustained GSK3β inhibition remains largely unknown. Here, we find that protein phosphatase 1 regulatory inhibitor subunit 14C (PPP1R14C) is upregulated in TNBC and relevant to poor prognosis in patients. Overexpression of PPP1R14C facilitates cell proliferation and the aggressive phenotype of TNBC cells, whereas the depletion of PPP1R14C elicits opposite effects. Moreover, PPP1R14C is phosphorylated and activated by protein kinase C iota (PRKCI) at Thr73. p‐PPP1R14C then represses Ser/Thr protein phosphatase type 1 (PP1) to retain GSK3β phosphorylation at high levels. Furthermore, p‐PPP1R14C recruits E3 ligase, TRIM25, toward the ubiquitylation and degradation of non‐phosphorylated GSK3β. Importantly, the blockade of PPP1R14C phosphorylation inhibits xenograft tumorigenesis and lung metastasis of TNBC cells. These findings provide a novel mechanism for sustained GSK3β inactivation in TNBC and suggest that PPP1R14C might be a potential therapeutic target.

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“…Indeed, inhibiting PP1 using RNAi or pharmacological inhibitors triggers MYC hyperphosphorylation, leading to chromatin eviction and MYC protein degradation (Dingar et al, 2018). Exploiting this PP1:PNUTS-MYC regulatory axis to target MYC destruction has promise; however, inhibiting PP1 catalytic activity is not a viable approach as PP1 has several protein substrates (Bollen et al, 2010;Casamayor and Arino, 2020;Cohen, 2002). Thus, to advance our understanding of how MYC is regulated by this phosphatase complex and to evaluate the potential for pharmacological disruption of MYC interaction with PP1:PNUTS to promote MYC degradation, we sought to delineate the molecular basis of this interaction.…”

Section: Introductionmentioning

confidence: 99%

The PNUTS-PAD domain recruits MYC to the PNUTS:PP1 phosphatase complex via the oncogenic MYC-MB0 region

Wei

Ahlner

Redel

et al. 2021

Preprint

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Despite MYC dysregulation in most human cancers, strategies to target this potent oncogenic driver remains an urgent unmet need. Recent evidence shows the PP1 phosphatase and its regulatory subunit PNUTS control MYC phosphorylation and stability, however the molecular basis remains unclear. Here we demonstrate that MYC interacts directly with PNUTS through the MYC homology Box 0 (MB0), a highly conserved region recently shown to be important for MYC oncogenic activity. MB0 interacts with PNUTS residues 1-148, a functional unit here termed, PNUTS amino-terminal domain (PAD). Using NMR spectroscopy we determined the solution structure of PAD, and characterised its interaction with MYC. Point mutations of residues at the MYC-PNUTS interface significantly weaken their interaction both in vitro and in vivo. These data demonstrate the MB0 binding pocket of the PAD represents an attractive site for pharmacological disruption of the MYC-PNUTS interaction.

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Controlling Ser/Thr protein phosphatase PP1 activity and function through interaction with regulatory subunits

Cited by 29 publications

References 230 publications

Mapping PP1c and Its Inhibitor 2 Interactomes Reveals Conserved and Specific Networks in Asexual and Sexual Stages of Plasmodium

Mapping PP1c and Its Inhibitor 2 Interactomes Reveals Conserved and Specific Networks in Asexual and Sexual Stages of Plasmodium

Protein phosphatase 1 regulatory inhibitor subunit 14C promotes triple‐negative breast cancer progression via sustaining inactive glycogen synthase kinase 3 beta

The PNUTS-PAD domain recruits MYC to the PNUTS:PP1 phosphatase complex via the oncogenic MYC-MB0 region

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