Erratum: PRL3 phosphatase active site is required for binding the putative magnesium transporter CNNM3

Zhang, Huizhi; Kozlov, Guennadi; Li, Xinlu; Wu, Howie; Gulerez, Irina; Gehring, Kalle

doi:10.1038/s41598-017-04855-7

Cited by 7 publications

(7 citation statements)

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“…As a second measure of phosphatase activity, we examined formation of the phosphocysteine intermediate upon incubation with a small molecule substrate, OMFP (22). As expected, Phos-tag SDS-PAGE analysis showed formation of the phosphocysteine intermediate upon incubation with a small molecule substrate by WT PRL3 and the R138E mutant, whereas the cysteine mutants were inactive (Fig.…”

Section: Mutagenesis Of the Prl3 Active Sitementioning

confidence: 54%

“…7). Indeed, in vitro incubation of PRL2 with small phosphate-containing compounds leads to partial cysteine phosphorylation (22). As PRL phosphatase activity is inhibited when bound to CNNM (13), one possibility is that phosphorylation acts as a switch to prevent re-association of PRLs following release.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies showed that substitution of the PRL3 catalytic cysteine by serine or alanine leads to loss of both phosphatase activity and CNNM binding (12,22). In protein phosphatases, the active site cysteine is present as a negatively charged thiolate so we reasoned that substitution of cysteine by aspartic acid might preserve CNNM-binding.…”

Section: Mutagenesis Of the Prl3 Active Sitementioning

confidence: 94%

“…It does not make direct contacts with CNNM but its mutation has a large effect on binding. Crystal structures of PRL-CNNM complexes show only minor conformational changes despite large differences in affinity (13,22). Similarly, disulfide bond formation with an adjacent cysteine leads to a ;500-fold loss of affinity with only modest structural changes (22,23).…”

Section: Crystal Structures Of Mutant Prl Complexesmentioning

confidence: 99%

“…CNNMs are membrane proteins with a transmembrane domain that transports Mg 21 and a cytosolic domain that binds PRLs (21). Binding is mediated by a conserved CNNM aspartic acid that acts as a pseudosubstrate and inserts into the PRL active site (13,22,23). There are four CNNM proteins in humans that bind with similar affinity to all three PRLs.…”

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confidence: 99%

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PRL3 pseudophosphatase activity is necessary and sufficient to promote metastatic growth

Kozlov

Funato

Chen

et al. 2020

Journal of Biological Chemistry

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Phosphatases of regenerating liver (PRLs) are markers of cancer and promote tumor growth. They have been implicated in a variety of biochemical pathways but the physiologically relevant target of phosphatase activity has eluded 20 years of investigation. Here, we show that PRL3 catalytic activity is not required in a mouse model of metastasis. PRL3 binds and inhibits CNNM4, a membrane protein associated with magnesium transport. Analysis of PRL3 mutants specifically defective in either CNNM-binding or phosphatase activity demonstrate that CNNM-binding is necessary and sufficient to promote tumor metastasis. As PRLs do have phosphatase activity, they are in fact pseudo-pseudophosphatases. Phosphatase activity leads to formation of phosphocysteine, which blocks CNNM-binding and may play a regulatory role. We show levels of PRL cysteine phosphorylation vary in response to culture conditions and in different tissues. Examination of related protein phosphatases shows the stability of phosphocysteine is a unique and evolutionarily conserved property of PRLs. The demonstration that PRL3 functions as a pseudophosphatase has important ramifications for the design of PRL inhibitors for cancer.

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Section: Mutagenesis Of the Prl3 Active Sitementioning

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Section: Mutagenesis Of the Prl3 Active Sitementioning

confidence: 94%

Section: Crystal Structures Of Mutant Prl Complexesmentioning

confidence: 99%

mentioning

confidence: 99%

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PRL3 pseudophosphatase activity is necessary and sufficient to promote metastatic growth

Kozlov

Funato

Chen

et al. 2020

Journal of Biological Chemistry

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PDK2 induces cisplatin-resistance in lung adenocarcinoma via transcriptional regulation of CNNM3

Yang

et al. 2018

Journal of Drug Targeting

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Keep it on the edge: The post-mitotic midbody as a polarity signal unit

Luján

Rubio

Varsano

et al. 2017

Communicative & Integrative Biology

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The maintenance of the epithelial architecture during tissue proliferation is achieved by apical positioning of the midbody after cell division. Consequently, midbody mislocalization contributes to epithelial architecture disruption, a fundamental event during epithelial tumorigenesis. Studies in 3D polarized epithelial MDCK or Caco2 cell models, where midbody misplacement leads to multiple ectopic but fully polarized lumen-containing cysts, revealed that this phenotype can be caused by 2 different scenarios: the loss of mitotic spindle orientation or the loss of asymmetric abscission. In addition, we have recently proposed a third cellular mechanism where the midbody mislocalization is achieved through cytokinesis acceleration driven by the cancer-promoting phosphatase of regenerating liver (PRL)-3. Here we critically review these findings, and we furthermore present new data indicating that midbodies themselves might act as signal unit for polarization since they can infer apical characteristics to a basal membrane.

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Erratum: PRL3 phosphatase active site is required for binding the putative magnesium transporter CNNM3

Abstract: A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper

Cited by 7 publications

References 0 publications

PRL3 pseudophosphatase activity is necessary and sufficient to promote metastatic growth

PRL3 pseudophosphatase activity is necessary and sufficient to promote metastatic growth

PDK2 induces cisplatin-resistance in lung adenocarcinoma via transcriptional regulation of CNNM3

Keep it on the edge: The post-mitotic midbody as a polarity signal unit

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