Drosophila awd, the homolog of human nm23, regulates FGF receptor levels and functions synergistically with shi/dynamin during tracheal development

Dammai, Vincent; Adryan, Boris; Lavenburg, Kim R.; Hsu, Tien

doi:10.1101/gad.1096903

Cited by 88 publications

(139 citation statements)

References 57 publications

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“…Cependant, celle-ci n'a pas été démontrée pour la protéine recombinante purifiée et n'est pas compatible avec la structure tridimensionnelle de l'enzyme. Des travaux sur les mécanismes moléculai-res de l'endocytose chez la drosophile et les cellules de mammifères suggèrent une coopération entre NM23 et la dynamine, GTPase indispensable à ce mécanisme, dans la modulation du signal induit par certains récepteurs, en particulier par le récepteur du FGF (fibroblast growth factor) [12]. Ainsi, l'absence de NM23 empêcherait le recyclage de ces récepteurs et prolongerait leur action.…”

Section: Nm23unclassified

NM23 et les genès Suppresseurs de métastases

2007

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Près de 90 % des décès des patients atteints de cancer sont dus aux métastases. Les mécanismes moléculaires précis impliqués dans la dissémination métastatique sont mal connus et leur compréhension devrait faire considérablement progresser la thérapie anti-cancé-reuse. L'existence de gènes contrôlant spécifiquement le potentiel métastatique a été rapportée pour la première fois avec la découverte du gène NM23 [1].> La dissémination métastatique est la cause majeure des décès dus au cancer. Les mécanis-mes capables de conférer à une cellule tumorale un pouvoir métastatique sont complexes et encore mal connus. Plusieurs hypothèses sont proposées dont l'existence de cellules à potentiel métastatique dès les premières étapes de la formation de la tumeur primitive. Ce potentiel serait dû à la dérégulation de gènes spécifiques capables de favoriser ou d'inhiber la dissémination métastatique. Ainsi, les GSM, « gènes suppresseurs de métastases », objets de cet article, sont définis par leur capacité à supprimer in vivo le développement des métastases sans affecter la croissance de la tumeur primitive. La plupart des GSM modulent les voies de signalisation mettant en jeu les protéines G et la voie des MAP-kinases. Chez l'homme, plusieurs études cliniques ont établi une corrélation inverse entre l'expression de ces gènes dans la tumeur primitive et la survie des patients. Les GSM modulent le potentiel métastatique d'une tumeur essentiellement via des mécanismes épigénétiques, ce qui suggère qu'une réactivation de leur expression endogène pourrait constituer une voie thérapeutique anti-métastatique prometteuse. Nous présen-terons dans cette synthèse les différents GSM connus actuellement, tout particulièrement NME (NM23), objet de nos recherches, ainsi que les voies de signalisation dans lesquelles ces gènes sont potentiellement impliqués. < Il s'agit de gènes suppresseurs de métastases, objets de cet article, mais il existe aussi des gènes dont les produits favorisent le processus métastatique, et qui pourraient intervenir de façon positive sur les mêmes voies. La formation d'une métastase (« métastatogenèse »), tumeur secondaire à distance de la tumeur primitive, nécessite que les cellules tumorales franchissent de nombreuses étapes (Figure 1) : (1) le détachement de la tumeur primitive ; (2) l'envahissement du stroma péritumoral (invasion) ; (3) l'entrée (intravasation) et la survie dans la circulation sanguine et/ou lymphatique ; (4) l'arrêt au niveau de l'endothélium d'un organe cible secondaire ; (5) l'extravasation dans le tissu environnant ; (6) la prolifé-ration locale au niveau du site secondaire ou colonisation métastatique conduisant à la formation des métastases cliniquement détectables appelées macrométastases. Cependant, la présence de cellules tumorales disséminées au niveau du site secondaire ne permet pas de prédire l'apparition de métastases. En effet, les cellules tumorales peuvent être présentes mais rester quiescentes (état de dormance tumorale). Ces cellules tumorales dormantes peuvent évoluer sous f...

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Section: Nm23unclassified

NM23 et les genès Suppresseurs de métastases

2007

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“…Mhc has also been shown to be involved in border cell migration (Borghese et al, 2006), while the isolation and characterization of Stam suggests that trafficking of Fgfr-containing vesicles plays an important role in efficient cell migration. Previous studies have also shown that Drosophila abnormal wing discs (awd), the homologue of human NM23, regulates Fgf receptor levels and functions synergistically with shibire (also known as dynamin) during tracheal development (Dammai et al, 2003). The exact biochemical functions of Awd and the vertebrate homologues remain to be elucidated.…”

Section: The Role Of Cell Migrationmentioning

confidence: 99%

“…How the spatially restricted Fgf ligand Bnl regulates cytoskeletal dynamics at the molecular level is a key question that remains rather obscure. Only very few zygotic mutations with altered Fgf signalling levels in tracheal cells have been identified (Hacohen et al, 1998;Dammai et al, 2003). This is mostly because large maternal stores exist of many of the important components of this process, which hinder genetic approaches to identifying these components in embryos.…”

Section: The Role Of Cell Migrationmentioning

confidence: 99%

Tracheal branching morphogenesis inDrosophila: new insights into cell behaviour and organ architecture

2008

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2055Our understanding of the molecular control of morphological processes has increased tremendously over recent years through the development and use of high resolution in vivo imaging approaches, which have enabled cell behaviour to be linked to molecular functions. Here we review how such approaches have furthered our understanding of tracheal branching morphogenesis in Drosophila, during which the control of cell invagination, migration, competition and rearrangement is accompanied by the sequential secretion and resorption of proteins into the apical luminal space, a vital step in the elaboration of the trachea's complex tubular network. We also discuss the similarities and differences between flies and vertebrates in branched organ formation that are becoming apparent from these studies. IntroductionBranching morphogenesis restructures epithelial sheets to give rise to organs of fascinating three-dimensional architecture, as exemplified by the adult lung, the kidney and the vasculature in humans. In Drosophila melanogaster, genetic studies have provided much insight into the regulatory networks that regulate the ordered formation of tracheal branches in the embryo, and into how the different branches coordinate their relative sizes, an issue that is of importance to the physical aspects of branched organ function (Affolter et al., 2003;Ghabrial et al., 2003;Uv et al., 2003). More recently, the development of live-imaging approaches in Drosophila have allowed researchers to take a deeper look at the behaviour of cells during the branching process, and have enabled events at the molecular level to be linked to the behaviour of individual cells or groups of cells.This combination of molecular genetics and live-imaging techniques has provided investigators with a unique opportunity to understand the morphological processes that occur during branching morphogenesis. This review focuses and builds on some of these recent insights, and assesses how they have led to a better understanding of the cellular and molecular processes that contribute to the transformation of simple, two-dimensional epithelial sheets into fascinating, three-dimensional tubular structures that can perform important functions in development and homeostasis. We focus here on the Drosophila tracheal system because several cellular and molecular paradigms, such as cell migration, competition and rearrangement, as well as the elaboration of a complex apical luminal environment, have recently been uncovered in this system that might serve related roles in the formation of other branched organs or tissues; these similarities might help us in the future to gain an even better understanding of how morphogenesis in general is regulated during development. Tracheal development in the fly embryoThe complex structure of the tracheal system consists of interconnected, metameric units of different-sized tubes that extend over the entire embryo shortly before hatching (Samakovlis et al., 1996b) (see Fig. 1, see also Movie 1 in the supplementary material)....

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“…Detailed analysis of awd loss-of-function mutants showed ectopic tracheal migration accompanied by overaccumulation of Breathless/FGFR on tracheal cell surfaces [48]. As the awd mutant phenotype was exacerbated in the shi/dynamin mutant background [48], it was concluded that AWD regulates tracheal cell motility by modulating FGFR levels through a dynamin-mediated pathway (Fig.…”

Section: Awd Regulates Neurotransmission Through Its Endocytic Functionmentioning

confidence: 99%

“…In axenic culture, NDPK knockdown alone now created a phenotype (despite substrate availability) whereby endocytosis and exocytosis of recycling vesicles budding from the plasma membrane were both unexpectedly accelerated, and yet these NDPKs knocked down single cells failed to retain sufficient imbibed nutrients and consequently displayed slower growth. Since NDPK/AWD is a very important regulator of GTP supply to enhance dynamin function (shi function, in flies) [48], the authors concluded that nutrient retention within the single cell interior was perturbed by lack of NDPK. Their measured reduction in the mass of nutrient accumulation implies a deficit in nutrient transfer from the plasma membrane to the machinery within the cell interior that utilizes imbibed nutrients.…”

Section: Nm23-x4 Function In Xenopus Retinal Developmentmentioning

confidence: 99%

Nucleoside diphosphate kinases (NDPKs) in animal development

Takács‐Vellai

Vellai

Farkas

et al. 2014

Cell. Mol. Life Sci.

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In textbooks of biochemistry, nucleoside diphosphate conversion to a triphosphate by nucleoside diphosphate 'kinases' (NDPKs, also named NME or NM23 proteins) merits a few lines of text. Yet this essential metabolic function, mediated by a multimeric phosphotransferase protein, has effects that lie beyond a simple housekeeping role. NDPKs attracted more attention when NM23-H1 was identified as the first metastasis suppressor gene. In this review, we examine these NDPK enzymes from a developmental perspective because of the tractable phenotypes found in simple animal models that point to common themes. The data suggest that NDPK enzymes control the availability of surface receptors to regulate cellsensing cues during cell migration. NDPKs regulate different forms of membrane enclosure that engulf dying cells during development. We suggest that NDPK enzymes have been essential for the regulated uptake of objects such as bacteria or micronutrients, and this evolutionarily conserved endocytic function contributes to their activity towards the regulation of metastasis.

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Drosophila awd, the homolog of human nm23, regulates FGF receptor levels and functions synergistically with shi/dynamin during tracheal development

Cited by 88 publications

References 57 publications

NM23 et les genès Suppresseurs de métastases

NM23 et les genès Suppresseurs de métastases

Tracheal branching morphogenesis inDrosophila: new insights into cell behaviour and organ architecture

Nucleoside diphosphate kinases (NDPKs) in animal development

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