International Journal of Molecular Sciences

Editorial

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8 pages, 458 KiB

Open AccessEditorial

The Complex Functions of the NME Family—A Matter of Location and Molecular Activity

by Uwe Schlattner

Int. J. Mol. Sci. 2021, 22(23), 13083; https://doi.org/10.3390/ijms222313083 - 3 Dec 2021

Cited by 8 | Viewed by 2523

Abstract

The family of NME proteins represents a quite complex group of multifunctional enzymes [...] Full article

(This article belongs to the Special Issue Selected Papers from the 11th International Conference on the NME/NDPK/NM23/AWD Gene Family (NME 2019))

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Research

Jump to: Editorial, Review

29 pages, 3489 KiB

Open AccessArticle

Loss of the Metastasis Suppressor NME1, But Not of Its Highly Related Isoform NME2, Induces a Hybrid Epithelial–Mesenchymal State in Cancer Cells

by Anda Huna, Béatrice Nawrocki-Raby, Teresita Padilla-Benavides, Julie Gavard, Sylvie Coscoy, David Bernard and Mathieu Boissan

Int. J. Mol. Sci. 2021, 22(7), 3718; https://doi.org/10.3390/ijms22073718 - 2 Apr 2021

Cited by 8 | Viewed by 4548

Abstract

Epithelial–mesenchymal transition (EMT) is important for the initial steps of metastasis. Although it is well accepted that the nucleoside diphosphate kinase NME1 is a metastasis suppressor, its effect on EMT remains poorly documented, as does that of its closely related isoform, NME2. Here, [...] Read more.

Epithelial–mesenchymal transition (EMT) is important for the initial steps of metastasis. Although it is well accepted that the nucleoside diphosphate kinase NME1 is a metastasis suppressor, its effect on EMT remains poorly documented, as does that of its closely related isoform, NME2. Here, by using gene silencing, inactivation and overexpression strategies in a variety of cellular models of cancer, we show that NME1 is a powerful inhibitor of EMT. Genetic manipulation of NME2, by contrast, had no effect on the EMT phenotype of cancer cells, indicating a specific function of NME1 in EMT regulation. Loss of NME1 in epithelial cancer cells resulted in a hybrid phenotype intermediate between epithelial and mesenchymal cells, which is known to be associated with cells with a highly metastatic character. Conversely, overexpression of NME1 in mesenchymal cancer cells resulted in a more epithelial phenotype. We found that NME1 expression was negatively associated with EMT markers in many human cancers and was reduced in human breast tumor cell lines with the aggressive ‘triple-negative’ phenotype when compared to human breast tumor cell lines positive for estrogen receptor. We show that NME1, but not NME2, is an inhibitor of essential concerted intracellular signaling pathways involved in inducing EMT, including the AKT and MAPK (ERK, p38, and JNK) pathways. Additionally, NME1 depletion considerably altered the distribution of E-cadherin, a gatekeeper of the epithelial phenotype, shifting it from the plasma membrane to the cytosol and resulting in less E-cadherin on the cell surface than in control cells. Functional aggregation and dispersion assays demonstrated that inactivation of NME1 decreases E-cadherin-mediated cell–cell adhesion. We conclude that NME1, but not NME2, acts specifically to inhibit EMT and prevent the earliest stages of metastasis. Full article

(This article belongs to the Special Issue Selected Papers from the 11th International Conference on the NME/NDPK/NM23/AWD Gene Family (NME 2019))

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21 pages, 9232 KiB

Open AccessArticle

Mammalian Homologue NME3 of DYNAMO1 Regulates Peroxisome Division

by Masanori Honsho, Yuichi Abe, Yuuta Imoto, Zee-Fen Chang, Hanna Mandel, Tzipora C. Falik-Zaccai and Yukio Fujiki

Int. J. Mol. Sci. 2020, 21(21), 8040; https://doi.org/10.3390/ijms21218040 - 28 Oct 2020

Cited by 14 | Viewed by 3303

Abstract

Peroxisomes proliferate by sequential processes comprising elongation, constriction, and scission of peroxisomal membrane. It is known that the constriction step is mediated by a GTPase named dynamin-like protein 1 (DLP1) upon efficient loading of GTP. However, mechanism of fuelling GTP to DLP1 remains [...] Read more.

Peroxisomes proliferate by sequential processes comprising elongation, constriction, and scission of peroxisomal membrane. It is known that the constriction step is mediated by a GTPase named dynamin-like protein 1 (DLP1) upon efficient loading of GTP. However, mechanism of fuelling GTP to DLP1 remains unknown in mammals. We earlier show that nucleoside diphosphate (NDP) kinase-like protein, termed dynamin-based ring motive-force organizer 1 (DYNAMO1), generates GTP for DLP1 in a red alga, Cyanidioschyzon merolae. In the present study, we identified that nucleoside diphosphate kinase 3 (NME3), a mammalian homologue of DYNAMO1, localizes to peroxisomes. Elongated peroxisomes were observed in cells with suppressed expression of NME3 and fibroblasts from a patient lacking NME3 due to the homozygous mutation at the initiation codon of NME3. Peroxisomes proliferated by elevation of NME3 upon silencing the expression of ATPase family AAA domain containing 1, ATAD1. In the wild-type cells expressing catalytically-inactive NME3, peroxisomes were elongated. These results suggest that NME3 plays an important role in peroxisome division in a manner dependent on its NDP kinase activity. Moreover, the impairment of peroxisome division reduces the level of ether-linked glycerophospholipids, ethanolamine plasmalogens, implying the physiological importance of regulation of peroxisome morphology. Full article

(This article belongs to the Special Issue Selected Papers from the 11th International Conference on the NME/NDPK/NM23/AWD Gene Family (NME 2019))

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14 pages, 6901 KiB

Open AccessArticle

The Impact of Drosophila Awd/NME1/2 Levels on Notch and Wg Signaling Pathways

by Giulia Serafini, Giorgia Giordani, Luca Grillini, Davide Andrenacci, Giuseppe Gargiulo and Valeria Cavaliere

Int. J. Mol. Sci. 2020, 21(19), 7257; https://doi.org/10.3390/ijms21197257 - 1 Oct 2020

Cited by 1 | Viewed by 3437

Abstract

Awd, the Drosophila homologue of NME1/2 metastasis suppressors, plays key roles in many signaling pathways. Mosaic analysis of the null awd^J2A4 allele showed that loss of awd gene function blocks Notch signaling and the expression of its target genes including the Wingless [...] Read more.

Awd, the Drosophila homologue of NME1/2 metastasis suppressors, plays key roles in many signaling pathways. Mosaic analysis of the null awd^J2A4 allele showed that loss of awd gene function blocks Notch signaling and the expression of its target genes including the Wingless (Wg/Wnt1) morphogen. We also showed that RNA interference (RNAi)-mediated awd silencing (awdi) in larval wing disc leads to chromosomal instability (CIN) and to Jun amino-terminal kinases (JNK)-mediated cell death. Here we show that this cell death is independent of p53 activity. Based on our previous finding showing that forced survival of awdi-CIN cells leads to aneuploidy without the hyperproliferative effect, we investigated the Wg expression in awdi wing disc cells. Interestingly, the Wg protein is expressed in its correct dorso-ventral domain but shows an altered cellular distribution which impairs its signaling. Further, we show that RNAi-mediated knock down of awd in wing discs does not affect Notch signaling. Thus, our analysis of the hypomorphic phenotype arising from awd downregulation uncovers a dose-dependent effect of Awd in Notch and Wg signaling. Full article

(This article belongs to the Special Issue Selected Papers from the 11th International Conference on the NME/NDPK/NM23/AWD Gene Family (NME 2019))

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15 pages, 1588 KiB

Open AccessArticle

Metastasis Suppressor NME1 Modulates Choice of Double-Strand Break Repair Pathways in Melanoma Cells by Enhancing Alternative NHEJ while Inhibiting NHEJ and HR

by Gemma Puts, Stuart Jarrett, Mary Leonard, Nicolette Matsangos, Devin Snyder, Ying Wang, Richard Vincent, Benjamin Portney, Rachel Abbotts, Lena McLaughlin, Michal Zalzman, Feyruz Rassool and David Kaetzel

Int. J. Mol. Sci. 2020, 21(16), 5896; https://doi.org/10.3390/ijms21165896 - 17 Aug 2020

Cited by 6 | Viewed by 3376

Abstract

Reduced NME1 expression in melanoma cell lines, mouse models of melanoma, and melanoma specimens in human patients is associated with increased metastatic activity. Herein, we investigate the role of NME1 in repair of double-stranded breaks (DSBs) and choice of double-strand break repair (DSBR) [...] Read more.

Reduced NME1 expression in melanoma cell lines, mouse models of melanoma, and melanoma specimens in human patients is associated with increased metastatic activity. Herein, we investigate the role of NME1 in repair of double-stranded breaks (DSBs) and choice of double-strand break repair (DSBR) pathways in melanoma cells. Using chromatin immunoprecipitation, NME1 was shown to be recruited rapidly and directly to DSBs generated by the homing endonuclease I-PpoI. NME1 was recruited to DSBs within 30 min, in concert with recruitment of ataxia-telangiectasia mutated (ATM) protein, an early step in DSBR complex formation, as well as loss of histone 2B. NME1 was detected up to 5 kb from the break site after DSB induction, suggesting a role in extending chromatin reorganization away from the repair site. shRNA-mediated silencing of NME1 expression led to increases in the homologous recombination (HR) and non-homologous end-joining (NHEJ) pathways of double-strand break repair (DSBR), and reduction in the low fidelity, alternative-NHEJ (A-NHEJ) pathway. These findings suggest low expression of NME1 drives DSBR towards higher fidelity pathways, conferring enhanced genomic stability necessary for rapid and error-free proliferation in invasive and metastatic cells. The novel mechanism highlighted in the current study appears likely to impact metastatic potential and therapy-resistance in advanced melanoma and other cancers. Full article

(This article belongs to the Special Issue Selected Papers from the 11th International Conference on the NME/NDPK/NM23/AWD Gene Family (NME 2019))

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12 pages, 2408 KiB

Open AccessArticle

NME3 Regulates Mitochondria to Reduce ROS-Mediated Genome Instability

by Chih-Wei Chen, Ning Tsao, Wei Zhang and Zee-Fen Chang

Int. J. Mol. Sci. 2020, 21(14), 5048; https://doi.org/10.3390/ijms21145048 - 17 Jul 2020

Cited by 12 | Viewed by 3623

Abstract

NME3 is a member of the nucleoside diphosphate kinase (NDPK) family that binds to the mitochondrial outer membrane to stimulate mitochondrial fusion. In this study, we showed that NME3 knockdown delayed DNA repair without reducing the cellular levels of nucleotide triphosphates. Further analyses [...] Read more.

NME3 is a member of the nucleoside diphosphate kinase (NDPK) family that binds to the mitochondrial outer membrane to stimulate mitochondrial fusion. In this study, we showed that NME3 knockdown delayed DNA repair without reducing the cellular levels of nucleotide triphosphates. Further analyses revealed that NME3 knockdown increased fragmentation of mitochondria, which in turn led to mitochondrial oxidative stress-mediated DNA single-strand breaks (SSBs) in nuclear DNA. Re-expression of wild-type NME3 or inhibition of mitochondrial fission markedly reduced SSBs and facilitated DNA repair in NME3 knockdown cells, while expression of N-terminal deleted mutant defective in mitochondrial binding had no rescue effect. We further showed that disruption of mitochondrial fusion by knockdown of NME4 or MFN1 also caused mitochondrial oxidative stress-mediated genome instability. In conclusion, the contribution of NME3 to redox-regulated genome stability lies in its function in mitochondrial fusion. Full article

(This article belongs to the Special Issue Selected Papers from the 11th International Conference on the NME/NDPK/NM23/AWD Gene Family (NME 2019))

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16 pages, 2506 KiB

Open AccessArticle

Role of the Ang2–Tie2 Axis in Vascular Damage Driven by High Glucose or Nucleoside Diphosphate Kinase B Deficiency

by Anupriya Chatterjee, Rachana Eshwaran, Hongpeng Huang, Di Zhao, Martina Schmidt, Thomas Wieland and Yuxi Feng

Int. J. Mol. Sci. 2020, 21(10), 3713; https://doi.org/10.3390/ijms21103713 - 25 May 2020

Cited by 7 | Viewed by 4041

Abstract

Ablation of nucleoside diphosphate kinase B (NDPK-B) in mice causes a breakdown of the neurovascular unit in the retina, mimicking diabetic retinopathy. The NDPK-B deficiency-induced vascular damage is mediated by excessive angiopoietin 2 (Ang2). Herein, the potential involvement of its receptor, Tie2, was [...] Read more.

Ablation of nucleoside diphosphate kinase B (NDPK-B) in mice causes a breakdown of the neurovascular unit in the retina, mimicking diabetic retinopathy. The NDPK-B deficiency-induced vascular damage is mediated by excessive angiopoietin 2 (Ang2). Herein, the potential involvement of its receptor, Tie2, was investigated. NDPK-B-deficient mouse retinas showed an upregulation of Tie2, specifically in the deep capillary layer. A similar upregulation of Tie2 was observed in cultured endothelial cells (ECs) from different origins upon NDPK-B depletion, whereas high glucose (HG) treatment did not alter Tie2 expression. Immunofluorescence staining and subcellular fractionation showed that the majority of Tie2 upregulation occurred at the plasma membrane. Similar to HG, however, NDPK-B depletion reduced Tie2 tyrosine phosphorylation. Compared to HG, a stronger increase of Ang2 was observed in NDPK-B depleted ECs. Treatment of ECs with soluble Tie2 or siRNA-mediated Tie2 knockdown attenuated NDPK-B depletion- but not HG-induced Ang2 upregulation. Like NDPK-B depletion, overexpression of recombinant Ang2 in ECs enhanced Ang2 secretion and concomitantly promoted the upregulation of Tie2. Thus, we identified a new mechanism showing that after reaching a threshold level of secretion, Ang2 sustains its own expression and secretion by a Tie2-dependent positive feedback loop. Full article

(This article belongs to the Special Issue Selected Papers from the 11th International Conference on the NME/NDPK/NM23/AWD Gene Family (NME 2019))

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19 pages, 3309 KiB

Open AccessArticle

The Potential Functional Roles of NME1 Histidine Kinase Activity in Neuroblastoma Pathogenesis

by Kevin Adam, Jacqueline Lesperance, Tony Hunter and Peter E. Zage

Int. J. Mol. Sci. 2020, 21(9), 3319; https://doi.org/10.3390/ijms21093319 - 7 May 2020

Cited by 27 | Viewed by 5762

Abstract

Neuroblastoma is the most common extracranial solid tumor in childhood. Gain of chromosome 17q material is found in >60% of neuroblastoma tumors and is associated with poor patient prognosis. The NME1 gene is located in the 17q21.3 region, and high NME1 expression is [...] Read more.

Neuroblastoma is the most common extracranial solid tumor in childhood. Gain of chromosome 17q material is found in >60% of neuroblastoma tumors and is associated with poor patient prognosis. The NME1 gene is located in the 17q21.3 region, and high NME1 expression is correlated with poor neuroblastoma patient outcomes. However, the functional roles and signaling activity of NME1 in neuroblastoma cells and tumors are unknown. NME1 and NME2 have been shown to possess histidine (His) kinase activity. Using anti-1- and 3-pHis specific monoclonal antibodies and polyclonal anti-pH118 NME1/2 antibodies, we demonstrated the presence of pH118-NME1/2 and multiple additional pHis-containing proteins in all tested neuroblastoma cell lines and in xenograft neuroblastoma tumors, supporting the presence of histidine kinase activity in neuroblastoma cells and demonstrating the potential significance of histidine kinase signaling in neuroblastoma pathogenesis. We have also demonstrated associations between NME1 expression and neuroblastoma cell migration and differentiation. Our demonstration of NME1 histidine phosphorylation in neuroblastoma and of the potential role of NME1 in neuroblastoma cell migration and differentiation suggest a functional role for NME1 in neuroblastoma pathogenesis and open the possibility of identifying new therapeutic targets and developing novel approaches to neuroblastoma therapy. Full article

(This article belongs to the Special Issue Selected Papers from the 11th International Conference on the NME/NDPK/NM23/AWD Gene Family (NME 2019))

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20 pages, 4268 KiB

Open AccessArticle

Bacillus anthracis’ PA₆₃ Delivers the Tumor Metastasis Suppressor Protein NDPK-A/NME1 into Breast Cancer Cells

by Ina Felix, Santosh K. Lomada, Holger Barth and Thomas Wieland

Int. J. Mol. Sci. 2020, 21(9), 3295; https://doi.org/10.3390/ijms21093295 - 6 May 2020

Cited by 5 | Viewed by 3692

Abstract

Some highly metastatic types of breast cancer show decreased intracellular levels of the tumor suppressor protein NME1, also known as nm23-H1 or nucleoside diphosphate kinase A (NDPK-A), which decreases cancer cell motility and metastasis. Since its activity is directly correlated with the overall [...] Read more.

Some highly metastatic types of breast cancer show decreased intracellular levels of the tumor suppressor protein NME1, also known as nm23-H1 or nucleoside diphosphate kinase A (NDPK-A), which decreases cancer cell motility and metastasis. Since its activity is directly correlated with the overall outcome in patients, increasing the cytosolic levels of NDPK-A/NME1 in such cancer cells should represent an attractive starting point for novel therapeutic approaches to reduce tumor cell motility and decrease metastasis. Here, we established the Bacillus anthracis protein toxins’ transport component PA₆₃ as transporter for the delivery of His-tagged human NDPK-A into the cytosol of cultured cells including human MDA-MB-231 breast cancer cells. The specifically delivered His₆-tagged NDPK-A was detected in MDA-MB-231 cells via Western blotting and immunofluorescence microscopy. The PA₆₃-mediated delivery of His₆-NDPK-A resulted in reduced migration of MDA-MB-231 cells, as determined by a wound-healing assay. In conclusion, PA₆₃ serves for the transport of the tumor metastasis suppressor NDPK-A/NME1 into the cytosol of human breast cancer cells In Vitro, which reduced the migratory activity of these cells. This approach might lead to development of novel therapeutic options. Full article

(This article belongs to the Special Issue Selected Papers from the 11th International Conference on the NME/NDPK/NM23/AWD Gene Family (NME 2019))

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19 pages, 4631 KiB

Open AccessArticle

The Subcellular Localization and Oligomerization Preferences of NME1/NME2 upon Radiation-Induced DNA Damage

by Martina Radić, Marko Šoštar, Igor Weber, Helena Ćetković, Neda Slade and Maja Herak Bosnar

Int. J. Mol. Sci. 2020, 21(7), 2363; https://doi.org/10.3390/ijms21072363 - 29 Mar 2020

Cited by 13 | Viewed by 5093

Abstract

Nucleoside diphosphate kinases (NDPK/NME/Nm23) are enzymes composed of subunits NME1/NDPK A and NME2/NDPK B, responsible for the maintenance of the cellular (d)NTP pool and involved in other cellular processes, such as metastasis suppression and DNA damage repair. Although eukaryotic NDPKs are active only [...] Read more.

Nucleoside diphosphate kinases (NDPK/NME/Nm23) are enzymes composed of subunits NME1/NDPK A and NME2/NDPK B, responsible for the maintenance of the cellular (d)NTP pool and involved in other cellular processes, such as metastasis suppression and DNA damage repair. Although eukaryotic NDPKs are active only as hexamers, it is unclear whether other NME functions require the hexameric form, and how the isoenzyme composition varies in different cellular compartments. To examine the effect of DNA damage on intracellular localization of NME1 and NME2 and the composition of NME oligomers in the nucleus and the cytoplasm, we used live-cell imaging and the FRET/FLIM technique. We showed that exogenous NME1 and NME2 proteins co-localize in the cytoplasm of non-irradiated cells, and move simultaneously to the nucleus after gamma irradiation. The FRET/FLIM experiments imply that, after DNA damage, there is a slight shift in the homomer/heteromer balance between the nucleus and the cytoplasm. Collectively, our results indicate that, after irradiation, NME1 and NME2 engage in mutual functions in the nucleus, possibly performing specific functions in their homomeric states. Finally, we demonstrated that fluorophores fused to the N-termini of NME polypeptides produce the largest FRET effect and thus recommend this orientation for use in similar studies. Full article

(This article belongs to the Special Issue Selected Papers from the 11th International Conference on the NME/NDPK/NM23/AWD Gene Family (NME 2019))

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Review

Jump to: Editorial, Research

14 pages, 1550 KiB

Open AccessReview

Emerging Molecular Connections between NM23 Proteins, Telomeres and Telomere-Associated Factors: Implications in Cancer Metastasis and Ageing

by Shalu Sharma, Antara Sengupta and Shantanu Chowdhury

Int. J. Mol. Sci. 2021, 22(7), 3457; https://doi.org/10.3390/ijms22073457 - 27 Mar 2021

Cited by 3 | Viewed by 3281

Abstract

The metastasis suppressor function of NM23 proteins is widely understood. Multiple enzymatic activities of NM23 proteins have also been identified. However, relatively less known interesting aspects are being revealed from recent developments that corroborate the telomeric interactions of NM23 proteins. Telomeres are known [...] Read more.

The metastasis suppressor function of NM23 proteins is widely understood. Multiple enzymatic activities of NM23 proteins have also been identified. However, relatively less known interesting aspects are being revealed from recent developments that corroborate the telomeric interactions of NM23 proteins. Telomeres are known to regulate essential physiological events such as metastasis, ageing, and cellular differentiation via inter-connected signalling pathways. Here, we review the literature on the association of NM23 proteins with telomeres or telomere-related factors, and discuss the potential implications of emerging telomeric functions of NM23 proteins. Further understanding of these aspects might be instrumental in better understanding the metastasis suppressor functions of NM23 proteins. Full article

(This article belongs to the Special Issue Selected Papers from the 11th International Conference on the NME/NDPK/NM23/AWD Gene Family (NME 2019))

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17 pages, 2871 KiB

Open AccessReview

Structure, Folding and Stability of Nucleoside Diphosphate Kinases

by Florian Georgescauld, Yuyu Song and Alain Dautant

Int. J. Mol. Sci. 2020, 21(18), 6779; https://doi.org/10.3390/ijms21186779 - 16 Sep 2020

Cited by 26 | Viewed by 4365

Abstract

Nucleoside diphosphate kinases (NDPK) are oligomeric proteins involved in the synthesis of nucleoside triphosphates. Their tridimensional structure has been solved by X-ray crystallography and shows that individual subunits present a conserved ferredoxin fold of about 140 residues in prokaryotes, archaea, eukaryotes and viruses. [...] Read more.

Nucleoside diphosphate kinases (NDPK) are oligomeric proteins involved in the synthesis of nucleoside triphosphates. Their tridimensional structure has been solved by X-ray crystallography and shows that individual subunits present a conserved ferredoxin fold of about 140 residues in prokaryotes, archaea, eukaryotes and viruses. Monomers are functionally independent from each other inside NDPK complexes and the nucleoside kinase catalytic mechanism involves transient phosphorylation of the conserved catalytic histidine. To be active, monomers must assemble into conserved head to tail dimers, which further assemble into hexamers or tetramers. The interfaces between these oligomeric states are very different but, surprisingly, the assembly structure barely affects the catalytic efficiency of the enzyme. While it has been shown that assembly into hexamers induces full formation of the catalytic site and stabilizes the complex, it is unclear why assembly into tetramers is required for function. Several additional activities have been revealed for NDPK, especially in metastasis spreading, cytoskeleton dynamics, DNA binding and membrane remodeling. However, we still lack the high resolution structural data of NDPK in complex with different partners, which is necessary for deciphering the mechanism of these diverse functions. In this review we discuss advances in the structure, folding and stability of NDPKs. Full article

(This article belongs to the Special Issue Selected Papers from the 11th International Conference on the NME/NDPK/NM23/AWD Gene Family (NME 2019))

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26 pages, 3633 KiB

Open AccessReview

NME/NM23/NDPK and Histidine Phosphorylation

by Kevin Adam, Jia Ning, Jeffrey Reina and Tony Hunter

Int. J. Mol. Sci. 2020, 21(16), 5848; https://doi.org/10.3390/ijms21165848 - 14 Aug 2020

Cited by 34 | Viewed by 7429

Abstract

The NME (Non-metastatic) family members, also known as NDPKs (nucleoside diphosphate kinases), were originally identified and studied for their nucleoside diphosphate kinase activities. This family of kinases is extremely well conserved through evolution, being found in prokaryotes and eukaryotes, but also diverges enough [...] Read more.

The NME (Non-metastatic) family members, also known as NDPKs (nucleoside diphosphate kinases), were originally identified and studied for their nucleoside diphosphate kinase activities. This family of kinases is extremely well conserved through evolution, being found in prokaryotes and eukaryotes, but also diverges enough to create a range of complexity, with homologous members having distinct functions in cells. In addition to nucleoside diphosphate kinase activity, some family members are reported to possess protein-histidine kinase activity, which, because of the lability of phosphohistidine, has been difficult to study due to the experimental challenges and lack of molecular tools. However, over the past few years, new methods to investigate this unstable modification and histidine kinase activity have been reported and scientific interest in this area is growing rapidly. This review presents a global overview of our current knowledge of the NME family and histidine phosphorylation, highlighting the underappreciated protein-histidine kinase activity of NME family members, specifically in human cells. In parallel, information about the structural and functional aspects of the NME family, and the knowns and unknowns of histidine kinase involvement in cell signaling are summarized. Full article

(This article belongs to the Special Issue Selected Papers from the 11th International Conference on the NME/NDPK/NM23/AWD Gene Family (NME 2019))

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18 pages, 1860 KiB

Open AccessReview

Molecular Basis of Mitochondrial and Peroxisomal Division Machineries

by Yuuta Imoto, Kie Itoh and Yukio Fujiki

Int. J. Mol. Sci. 2020, 21(15), 5452; https://doi.org/10.3390/ijms21155452 - 30 Jul 2020

Cited by 18 | Viewed by 4892

Abstract

Mitochondria and peroxisomes are ubiquitous subcellular organelles that are highly dynamic and possess a high degree of plasticity. These organelles proliferate through division of pre-existing organelles. Studies on yeast, mammalian cells, and unicellular algae have led to a surprising finding that mitochondria and [...] Read more.

Mitochondria and peroxisomes are ubiquitous subcellular organelles that are highly dynamic and possess a high degree of plasticity. These organelles proliferate through division of pre-existing organelles. Studies on yeast, mammalian cells, and unicellular algae have led to a surprising finding that mitochondria and peroxisomes share the components of their division machineries. At the heart of the mitochondrial and peroxisomal division machineries is a GTPase dynamin-like protein, Dnm1/Drp1, which forms a contractile ring around the neck of the dividing organelles. During division, Dnm1/Drp1 functions as a motor protein and constricts the membrane. This mechanochemical work is achieved by utilizing energy from GTP hydrolysis. Over the last two decades, studies have focused on the structure and assembly of Dnm1/Drp1 molecules around the neck. However, the regulation of GTP during the division of mitochondrion and peroxisome is not well understood. Here, we review the current understanding of Dnm1/Drp1-mediated divisions of mitochondria and peroxisomes, exploring the mechanisms of GTP regulation during the Dnm1/Drp1 function, and provide new perspectives on their potential contribution to mitochondrial and peroxisomal biogenesis. Full article

(This article belongs to the Special Issue Selected Papers from the 11th International Conference on the NME/NDPK/NM23/AWD Gene Family (NME 2019))

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