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MK-STYX, a catalytically inactive phosphatase regulating mitochondrially dependent apoptosis.

ABSTRACT: Evasion of apoptosis is a significant problem affecting an array of cancers. In order to identify novel regulators of apoptosis, we performed an RNA interference (RNAi) screen against all kinases and phosphatases in the human genome. We identified MK-STYX (STYXL1), a catalytically inactive phosphatase with homology to the mitogen-activated protein kinase (MAPK) phosphatases. Despite this homology, MK-STYX knockdown does not significantly regulate MAPK signaling in response to growth factors or apoptotic stimuli. Rather, RNAi-mediated knockdown of MK-STYX inhibits cells from undergoing apoptosis induced by cellular stressors activating mitochondrion-dependent apoptosis. This MK-STYX phenotype mimics the loss of Bax and Bak, two potent guardians of mitochondrial apoptotic potential. Similar to loss of both Bax and Bak, cells without MK-STYX expression are unable to release cytochrome c. Proapoptotic members of the BCL-2 family (Bax, Bid, and Bim) are unable to trigger cytochrome c release in MK-STYX-depleted cells, placing the apoptotic deficiency at the level of mitochondrial outer membrane permeabilization (MOMP). MK-STYX was found to localize to the mitochondria but is neither released from the mitochondria upon apoptotic stress nor proximal to the machinery currently known to control MOMP, indicating that MK-STYX regulates MOMP using a distinct mechanism.

SUBMITTER: Niemi NM

PROVIDER: S-EPMC3135289 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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MK-STYX, a catalytically inactive phosphatase regulating mitochondrially dependent apoptosis.

Niemi Natalie M NM Lanning Nathan J NJ Klomp Jeff A JA Tait Stephen W SW Xu Yong Y Dykema Karl J KJ Murphy Leon O LO Gaither L Alex LA Xu H Eric HE Furge Kyle A KA Green Douglas R DR MacKeigan Jeffrey P JP

Molecular and cellular biology 20110124 7

Evasion of apoptosis is a significant problem affecting an array of cancers. In order to identify novel regulators of apoptosis, we performed an RNA interference (RNAi) screen against all kinases and phosphatases in the human genome. We identified MK-STYX (STYXL1), a catalytically inactive phosphatase with homology to the mitogen-activated protein kinase (MAPK) phosphatases. Despite this homology, MK-STYX knockdown does not significantly regulate MAPK signaling in response to growth factors or a ...[more]

PMID: 21262771

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Project description:The dual specificity phosphatase (DUSP) family has catalytically inactive members, called pseudophosphatases. They have mutations in their catalytic motifs that render them enzymatically inactive. This study analyzes the significance of two pseudophosphatases, MK-STYX [MAPK (mitogen-activated protein kinase phosphoserine/threonine/tyrosine-binding protein]) and STYX (serine/threonine/tyrosine-interacting protein), throughout their evolution and provides measurements and comparison of their evolutionary conservation. Phylogenetic trees were constructed to show any deviation from various species evolutionary paths. Data was collected on a large set of proteins that have either one of the two domains of MK-STYX, the DUSP domain or the cdc-25 homology (CH2) /rhodanese-like domain. The distance between species pairs for MK-STYX or STYX and Ka/Ks ratio were calculated. In addition, both pseudophosphatases were ranked among a large set of related proteins, including the active homologs of MK-STYX, MKP (MAPK phosphatase)-1 and MKP-3. MK-STYX had one of the highest species-species protein distances and was under weaker purifying selection pressure than most proteins with its domains. In contrast, the protein distances of STYX were lower than 82% of the DUSP-containing proteins and was under one of the strongest purifying selection pressures. However, there was similar selection pressure on the N-terminal sequences of MK-STYX, STYX, MKP-1, and MKP-3. We next perform statistical coupling analysis, a process that reveals interconnected regions within the proteins. We find that while MKP-1,-3, and STYX all have 2 functional units (sectors), MK-STYX only has one, and that MK-STYX is similar to MKP-3 in the evolutionary coupling of the active site and KIM domain. Within those two domains, the mean coupling is also most similar for MK-STYX and MKP-3. This study reveals striking distinctions between the evolutionary patterns of MK-STYX and STYX, suggesting a very specific role for each pseudophosphatase, further highlighting the relevance of these atypical members of DUSP as signaling regulators. Therefore, our study provides computational evidence and evolutionary reasons to further explore the properties of pseudophosphatases, in particular MK-STYX and STYX.

Project description:X-linked myotubular myopathy (XLMTM) is a congenital disorder caused by mutations of the myotubularin gene, MTM1. Myotubularin belongs to a large family of conserved lipid phosphatases that include both catalytically active and inactive myotubularin-related proteins (i.e., "MTMRs"). Biochemically, catalytically inactive MTMRs have been shown to form heteroligomers with active members within the myotubularin family through protein-protein interactions. However, the pathophysiological significance of catalytically inactive MTMRs remains unknown in muscle. By in vitro as well as in vivo studies, we have identified that catalytically inactive myotubularin-related protein 12 (MTMR12) binds to myotubularin in skeletal muscle. Knockdown of the mtmr12 gene in zebrafish resulted in skeletal muscle defects and impaired motor function. Analysis of mtmr12 morphant fish showed pathological changes with central nucleation, disorganized Triads, myofiber hypotrophy and whorled membrane structures similar to those seen in X-linked myotubular myopathy. Biochemical studies showed that deficiency of MTMR12 results in reduced levels of myotubularin protein in zebrafish and mammalian C2C12 cells. Loss of myotubularin also resulted in reduction of MTMR12 protein in C2C12 cells, mice and humans. Moreover, XLMTM mutations within the myotubularin interaction domain disrupted binding to MTMR12 in cell culture. Analysis of human XLMTM patient myotubes showed that mutations that disrupt the interaction between myotubularin and MTMR12 proteins result in reduction of both myotubularin and MTMR12. These studies strongly support the concept that interactions between myotubularin and MTMR12 are required for the stability of their functional protein complex in normal skeletal muscles. This work highlights an important physiological function of catalytically inactive phosphatases in the pathophysiology of myotubular myopathy and suggests a novel therapeutic approach through identification of drugs that could stabilize the myotubularin-MTMR12 complex and hence ameliorate this disorder.

Dataset Information

MK-STYX, a catalytically inactive phosphatase regulating mitochondrially dependent apoptosis.

Publications

MK-STYX, a catalytically inactive phosphatase regulating mitochondrially dependent apoptosis.

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