Metal-dependent Ser/Thr protein phosphatase PPM family: Evolution, structures, diseases and inhibitors

Kamada, Rui; Kudoh, Fuki; Ito, Shogo; Tani, Itsumi; Janairo, Jose Isagani B.; Omichinski, James G.; Sakaguchi, Kazuyasu

doi:10.1016/j.pharmthera.2020.107622

Cited by 72 publications

(73 citation statements)

References 177 publications

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“…Overexpressing wild-type Nil or the human PPM1B homolog of Nil restored phosphatase activity in nil 1 mutant eye discs (Figure 2H,I). Multiple sequence alignment pointed to aspartate-231 of Nil as an acidic residue critical for metal binding and phosphatase activity (Kamada et al, 2020). Mutation of this aspartate residue to asparagine generated the Nil D231N point mutant; its expression in nil 1 mutant eye discs failed to restore phosphatase activity (Figure 2J).…”

Section: Resultsmentioning

confidence: 99%

“…In a targeted screen, we identified CG6036, a member of the PPM family of protein phosphatases as critical for controling the phospho-switch on Acn-S437. PPM-type phosphatases are dependent on Mg 2+ or Mn 2+ as co-factor for their activity (Kamada et al, 2020). They are not inhibited by the broad-spectrum phosphatase inhibitor okadaic acid, in contrast to PPP-type phosphatases and do not require the regulatory subunits characteristic for PPP-type phosphatases.…”

Section: Introductionmentioning

confidence: 99%

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A phospho-switch at Acinus-Serine⁴³⁷ controls autophagic responses to Cadmium exposure and neurodegenerative stress

Nandi

Zaidi

Tracy

et al. 2021

Preprint

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Neuronal health depends on quality control functions of autophagy, but mechanisms regulating neuronal autophagy are poorly understood. Previously, we showed that in Drosophila starvation-independent quality control autophagy is regulated by Acinus and the Cdk5-dependent phosphorylation of its serine437 (Nandi et al., 2017). Here, we identify the phosphatase that counterbalances this activity and provides for the dynamic nature of Acinus-S437 phosphorylation. A genetic screen identified six phosphatases that genetically interacted with an Acinus gain-of-function model. Among these, loss of function of only one, the PPM-type phosphatase Nil (CG6036), enhanced pS437-Acinus levels. Cdk5-dependent phosphorylation of Acinus serine437 in nil1 animals elevates neuronal autophagy and reduces the accumulation of polyQ proteins in a Drosophila Huntington's disease model. Consistent with previous findings that Cd2+ inhibits PPM-type phosphatases, Cd2+-exposure elevated Acinus-serine437 phosphorylation which was necessary for increased neuronal autophagy and protection against Cd2+-induced cytotoxicity. Together, our data establish the Acinus-S437 phospho-switch as critical integrator of multiple stress signals regulating neuronal autophagy.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A phospho-switch at Acinus-Serine⁴³⁷ controls autophagic responses to Cadmium exposure and neurodegenerative stress

Nandi

Zaidi

Tracy

et al. 2021

Preprint

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“…Previous studies demonstrated that malfunction of the PPM family was correlated with tumors, metabolic diseases and other various diseases. Protein phosphatases control diverse cellular events, including proliferation, differentiation, and stress response, by regulating reversible protein phosphorylation (the most important posttranslational modification) [ 6 ]. PPM1D, a member of the PP2C family that is recognized as a common oncogene, is related to many different human tumors, including adult supratentorial diffuse astrocytoma and oligodendroglioma, high-grade glioma [ 7 ], non-small-cell lung cancer [ 8 ] and lymph node metastasis, as well as esophageal squamous cell carcinoma (ESCC) [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

“…Mutation, overexpression or deletion of PPM phosphatase genes can cause abnormal cellular responses, leading to various human diseases, including cancer. Therefore, members of the PPM family are considered potential targets for cancer therapy [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Prognostic and immunological potential of PPM1G in hepatocellular carcinoma

Lin

Yang

2021

Aging

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“…In contrast to the PPP family, PPM family members have additional domains and conserved motifs that may help substrate specificity instead of regulatory subunits in the PPP family. The PPM family contains Mg 2+ /Mn 2+ ions in their active center, and work as monomeric enzymes with individual unique loops/inserts in each catalytic domain [12][13][14]. Although the sequences of PPMs differ from those of the PPP subfamily, their crystal structures reveal great structural similarity between them [15].…”

Section: Introductionmentioning

confidence: 99%

Methods for Identification of Substrates/Inhibitors of FCP/SCP Type Protein Ser/Thr Phosphatases

et al. 2020

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Protein phosphorylation is the most widespread type of post-translational modification and is properly controlled by protein kinases and phosphatases. Regarding the phosphorylation of serine (Ser) and threonine (Thr) residues, relatively few protein Ser/Thr phosphatases control the specific dephosphorylation of numerous substrates, in contrast with Ser/Thr kinases. Recently, protein Ser/Thr phosphatases were reported to have rigid substrate recognition and exert various biological functions. Therefore, identification of targeted proteins by individual protein Ser/Thr phosphatases is crucial to clarify their own biological functions. However, to date, information on the development of methods for identification of the substrates of protein Ser/Thr phosphatases remains scarce. In turn, substrate-trapping mutants are powerful tools to search the individual substrates of protein tyrosine (Tyr) phosphatases. This review focuses on the development of novel methods for the identification of Ser/Thr phosphatases, especially small C-terminal domain phosphatase 1 (Scp1), using peptide-displayed phage library with AlF4−/BeF3−, and discusses the identification of putative inhibitors.

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Metal-dependent Ser/Thr protein phosphatase PPM family: Evolution, structures, diseases and inhibitors

Cited by 72 publications

References 177 publications

A phospho-switch at Acinus-Serine⁴³⁷ controls autophagic responses to Cadmium exposure and neurodegenerative stress

A phospho-switch at Acinus-Serine⁴³⁷ controls autophagic responses to Cadmium exposure and neurodegenerative stress

Prognostic and immunological potential of PPM1G in hepatocellular carcinoma

Methods for Identification of Substrates/Inhibitors of FCP/SCP Type Protein Ser/Thr Phosphatases

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Metal-dependent Ser/Thr protein phosphatase PPM family: Evolution, structures, diseases and inhibitors

Cited by 72 publications

References 177 publications

A phospho-switch at Acinus-Serine437 controls autophagic responses to Cadmium exposure and neurodegenerative stress

A phospho-switch at Acinus-Serine437 controls autophagic responses to Cadmium exposure and neurodegenerative stress

Prognostic and immunological potential of PPM1G in hepatocellular carcinoma

Methods for Identification of Substrates/Inhibitors of FCP/SCP Type Protein Ser/Thr Phosphatases

Contact Info

Product

Resources

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A phospho-switch at Acinus-Serine⁴³⁷ controls autophagic responses to Cadmium exposure and neurodegenerative stress

A phospho-switch at Acinus-Serine⁴³⁷ controls autophagic responses to Cadmium exposure and neurodegenerative stress