The Pseudophosphatase MK-STYX Physically and Genetically Interacts with the Mitochondrial Phosphatase PTPMT1

Niemi, Natalie M.; Sacoman, Juliana L.; Westrate, Laura M.; Gaither, L. Alex; Lanning, Nathan; Martin, Katie R.; MacKeigan, Jeffrey P.

doi:10.1371/journal.pone.0093896

Cited by 23 publications

(39 citation statements)

References 30 publications

(50 reference statements)

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“…Recently, a model was provided for the molecular mechanism by which MK-STYX controls apoptosis, suggesting that MK-STYX negatively regulates PTPM1 (PTP localized to the mitochondrion 1). MK-STYX interacts with PTPM1 and inhibits its catalytic activity, regulating cell viability [38] . Such interactions between a pseudophosphatase and an active phosphatase are also seen among the myotubularin phosphatases [38] .…”

Section: Discussionmentioning

confidence: 99%

“…MK-STYX interacts with PTPM1 and inhibits its catalytic activity, regulating cell viability [38] . Such interactions between a pseudophosphatase and an active phosphatase are also seen among the myotubularin phosphatases [38] . However, binding of the myotubularin pseudophosphatase to its active homolog enhances phosphatase activity [48] .…”

Section: Discussionmentioning

confidence: 99%

“…Despite being catalytically inactive, MK-STYX plays a role in a number of important cellular pathways [34] – [36] , including inhibition of apoptosis and stress granule formation [34] , [35] , [37] . The functionality of MK-STYX is underexplored and still remains elusive; however, as with active MKP homologs, determining its interaction partners has helped elucidate some of the functions of MK-STYX [34] , [38] . In earlier studies concerning the cellular function of MK-STYX, we discovered that it binds G3BP-1 (Ras-GTPase activating protein SH3 domain binding protein-1), which regulates both the Ras signaling pathway and stress granule assembly [1] .…”

Section: Introductionmentioning

confidence: 99%

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The Pseudophosphatase MK-STYX Induces Neurite-Like Outgrowths in PC12 Cells

et al. 2014

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The rat pheochromocytoma PC12 cell line is a widely used system to study neuronal differentiation for which sustained activation of the extracellular signaling related kinase (ERK) pathway is required. Here, we investigate the function of MK-STYX [MAPK (mitogen-activated protein kinase) phosphoserine/threonine/tyrosine-binding protein] in neuronal differentiation. MK-STYX is a member of the MAPK phosphatase (MKP) family, which is generally responsible for dephosphorylating the ERKs. However, MK-STYX lacks catalytic activity due to the absence of the nucleophilic cysteine in the active site signature motif HC(X5)R that is essential for phosphatase activity. Despite being catalytically inactive, MK-STYX has been shown to play a role in important cellular pathways, including stress responses. Here we show that PC12 cells endogenously express MK-STYX. In addition, MK-STYX, but not its catalytically active mutant, induced neurite-like outgrowths in PC12 cells. Furthermore, MK-STYX dramatically increased the number of cells with neurite extensions in response to nerve growth factor (NGF), whereas the catalytically active mutant did not. MK-STYX continued to induce neurites in the presence of a MEK (MAP kinase kinase) inhibitor suggesting that MK-STYX does not act through the Ras-ERK/MAPK pathway but is involved in another pathway whose inactivation leads to neuronal differentiation. RhoA activity assays indicated that MK-STYX induced extensions through the Rho signaling pathway. MK-STYX decreased RhoA activation, whereas RhoA activation increased when MK-STYX was down-regulated. Furthermore, MK-STYX affected downstream players of RhoA such as the actin binding protein cofilin. The presence of MK-STYX decreased the phosphorylation of cofilin in non NGF stimulated cells, but increased its phosphorylation in NGF stimulated cells, whereas knocking down MK-STYX caused an opposite effect. Taken together our data suggest that MK-STYX may be a regulator of RhoA signaling, and implicate this pseudophosphatase as a regulator of neuronal differentiation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Pseudophosphatase MK-STYX Induces Neurite-Like Outgrowths in PC12 Cells

et al. 2014

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“…This is especially the case in the myotubularin (MTM) family, with six inactive phosphatases out of 15 protein members (Table ). Protein–protein interactions with active phosphatases or with phosphatase substrate or regulatory proteins seem to constitute a major mechanism by which pseudophosphatases exert their functions . In addition, many enzymes from the PTPome target either pSer/pThr or other molecules as diverse as the CAP structure of RNA, phosphoinositides, or phosphatidylglycerol phosphate.…”

Section: Introductionmentioning

confidence: 99%

The extended human PTPome: a growing tyrosine phosphatase family

Alonso

Pulido

2015

The FEBS Journal

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Tyr phosphatases are, by definition, enzymes that dephosphorylate phospho‐Tyr (pTyr) from proteins. This activity is found in several structurally diverse protein families, including the protein Tyr phosphatase (PTP), arsenate reductase, rhodanese, haloacid dehalogenase (HAD) and His phosphatase (HP) families. Most of these families include members with substrate specificity for non‐pTyr substrates, such as phospho‐Ser/phospho‐Thr, phosphoinositides, phosphorylated carbohydrates, mRNAs, or inorganic moieties. A Cys is essential for catalysis in PTPs, rhodanese and arsenate reductase enzymes, whereas this work is performed by an Asp in HAD phosphatases and by a His in HPs, via a catalytic mechanism shared by all of the different families. The category that contains most Tyr phosphatases is the PTP family, which, although it received its name from this activity, includes Ser, Thr, inositide, carbohydrate and RNA phosphatases, as well as some inactive pseudophosphatase proteins. Here, we propose an extended collection of human Tyr phosphatases, which we call the extended human PTPome. The addition of new members (SACs, paladin, INPP4s, TMEM55s, SSU72, and acid phosphatases) to the currently categorized PTP group of enzymes means that the extended human PTPome contains up to 125 proteins, of which ~ 40 are selective for pTyr. We set criteria to ascribe proteins to the extended PTPome, and summarize the more important features of the new PTPome members in the context of their phosphatase activity and their relationship with human disease.

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“…This pseudophosphatase has the potential to affect different proteins/pathways, including ERKs (Reiterer et al, 2013), PTPMP1 (Niemi et al, 2014) and Ras signaling through interaction with G3BP‐1 (Barr et al, 2013). Downregulation of Styx caused an increase in 4E‐BP1 phosphorylation at T37/46, similarly to what was observed after APP depletion.…”

Section: Discussionmentioning

confidence: 99%

Amyloid Precursor Protein (APP) Affects Global Protein Synthesis in Dividing Human Cells

Sobol¹,

Galluzzo²,

Liang³

et al. 2015

Journal Cellular Physiology

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Hypoxic non‐small cell lung cancer (NSCLC) is dependent on Notch‐1 signaling for survival. Targeting Notch‐1 by means of γ‐secretase inhibitors (GSI) proved effective in killing hypoxic NSCLC. Post‐mortem analysis of GSI‐treated, NSCLC‐burdened mice suggested enhanced phosphorylation of 4E‐BP1 at threonines 37/46 in hypoxic tumor tissues. In vitro dissection of this phenomenon revealed that Amyloid Precursor Protein (APP) inhibition was responsible for a non‐canonical 4E‐BP1 phosphorylation pattern rearrangement—a process, in part, mediated by APP regulation of the pseudophosphatase Styx. Upon APP depletion we observed modifications of eIF‐4F composition indicating increased recruitment of eIF‐4A to the mRNA cap. This phenomenon was supported by the observation that cells with depleted APP were partially resistant to silvestrol, an antibiotic that interferes with eIF‐4A assembly into eIF‐4F complexes. APP downregulation in dividing human cells increased the rate of global protein synthesis, both cap‐ and IRES‐dependent. Such an increase seemed independent of mTOR inhibition. After administration of Torin‐1, APP downregulation and Mechanistic Target of Rapamycin Complex 1 (mTORC‐1) inhibition affected 4E‐BP1 phosphorylation and global protein synthesis in opposite fashions. Additional investigations indicated that APP operates independently of mTORC‐1. Key phenomena described in this study were reversed by overexpression of the APP C‐terminal domain. The presented data suggest that APP may be a novel regulator of protein synthesis in dividing human cells, both cancerous and primary. Furthermore, APP appears to affect translation initiation using mechanisms seemingly dissimilar to mTORC‐1 regulation of cap‐dependent protein synthesis. J. Cell. Physiol. 230: 1064–1074, 2015. © 2014 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.

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The Pseudophosphatase MK-STYX Physically and Genetically Interacts with the Mitochondrial Phosphatase PTPMT1

Cited by 23 publications

References 30 publications

The Pseudophosphatase MK-STYX Induces Neurite-Like Outgrowths in PC12 Cells

The Pseudophosphatase MK-STYX Induces Neurite-Like Outgrowths in PC12 Cells

The extended human PTPome: a growing tyrosine phosphatase family

Amyloid Precursor Protein (APP) Affects Global Protein Synthesis in Dividing Human Cells

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