Drosophila RET contains an active tyrosine kinase and elicits neurotrophic activities in mammalian cells
TL;DR: Initial biochemical and functional characterization of the dRET protein in cell culture systems indicate significant conservation between the biological effects elicited by the human and Drosophila RET kinases, and suggest functions for dRET in neuronal differentiation in the fly.
About: This article is published in FEBS Letters.The article was published on 2005-07-04 and is currently open access. It has received 32 citations till now. The article focuses on the topics: Glial cell line-derived neurotrophic factor & Tyrosine phosphorylation.
Citations
More filters
TL;DR: It is reported that a signaling active version of Ret (RetMEN2B) rescues muscle degeneration, disintegration of mitochondria and ATP content of Pink1 mutants, providing a novel mechanism underlying Ret‐mediated cell protection in a situation relevant for human PD.
Abstract: Parkinson's disease (PD)-associated Pink1 and Parkin proteins are believed to function in a common pathway controlling mitochondrial clearance and trafficking. Glial cell line-derived neurotrophic factor (GDNF) and its signaling receptor Ret are neuroprotective in toxin-based animal models of PD. However, the mechanism by which GDNF/Ret protects cells from degenerating remains unclear. We investigated whether the Drosophila homolog of Ret can rescue Pink1 and park mutant phenotypes. We report that a signaling active version of Ret (RetMEN2B) rescues muscle degeneration, disintegration of mitochondria and ATP content of Pink1 mutants. Interestingly, corresponding phenotypes of park mutants were not rescued, suggesting that the phenotypes of Pink1 and park mutants have partially different origins. In human neuroblastoma cells, GDNF treatment rescues morphological defects of PINK1 knockdown, without inducing mitophagy or Parkin recruitment. GDNF also rescues bioenergetic deficits of PINK knockdown cells. Furthermore, overexpression of RetMEN2B significantly improves electron transport chain complex I function in Pink1 mutant Drosophila. These results provide a novel mechanism underlying Ret-mediated cell protection in a situation relevant for human PD.
65 citations
Cites background from "Drosophila RET contains an active t..."
...The signaling properties and functions of Drosophila Ret are not characterized in great detail, but it is structurally homologous to mammalian Ret and can, to some extent, activate the same signaling pathways (Abrescia et al, 2005)....
[...]
TL;DR: A mouse genetic study reveals a novel cell-survival role for the Parkinson's disease-associated gene DJ-1 in dopaminergic neurons that have reduced support from endogenous survival factors.
Abstract: The mechanisms underlying the selective death of substantia nigra (SN) neurons in Parkinson disease (PD) remain elusive. While inactivation of DJ-1, an oxidative stress suppressor, causes PD, animal models lacking DJ-1 show no overt dopaminergic (DA) neuron degeneration in the SN. Here, we show that aging mice lacking DJ-1 and the GDNF-receptor Ret in the DA system display an accelerated loss of SN cell bodies, but not axons, compared to mice that only lack Ret signaling. The survival requirement for DJ-1 is specific for the GIRK2-positive subpopulation in the SN which projects exclusively to the striatum and is more vulnerable in PD. Using Drosophila genetics, we show that constitutively active Ret and associated Ras/ERK, but not PI3K/Akt, signaling components interact genetically with DJ-1. Double loss-of-function experiments indicate that DJ-1 interacts with ERK signaling to control eye and wing development. Our study uncovers a conserved interaction between DJ-1 and Ret-mediated signaling and a novel cell survival role for DJ-1 in the mouse. A better understanding of the molecular connections between trophic signaling, cellular stress and aging could uncover new targets for drug development in PD.
60 citations
Cites background from "Drosophila RET contains an active t..."
...Although the effects of Ret signaling on GIRK2 have not been studied, it is tempting to speculate that the modulation of Ras/Mapk signaling by Ret and DJ-1 also affects GIRK2 function and vulnerability of dopaminergic neurons....
[...]
...gous to mammalian Ret [32] and exhibits activities associated with human Ret both in tissue culture cells and during Drosophila eye development [33,34]....
[...]
...The observed frequencies are shown for the different genotypes (n.115 wings analyzed per animal). doi:10.1371/journal.pbio.1000349.g008 PLoS Biology | www.plosbiology.org 10 April 2010 | Volume 8 | Issue 4 | e1000349 novel DJ-1B2/2 phenotype in the unchallenged fly and suggest that DJ-1B cooperates with Ras/Mapk signalling during photoreceptor neuron and wing imaginal disc development....
[...]
...To gain insights into the mechanism(s) underlying the genetic interaction between Ret and DJ-1, we investigated the capacity of fly DJ-1A/B to genetically modify pathways that are known to mediate Ret function: PI3K/Akt and Ras/Mapk [33]....
[...]
...PLoS Biology | www.plosbiology.org 5 April 2010 | Volume 8 | Issue 4 | e1000349 Genetic Interaction of DJ-1A/B and dRet in Drosophila Eye Development To obtain independent evidence for genetic interaction between Ret and DJ-1 and to begin characterizing the underlying intracellular pathways, we used the developing Drosophila eye system, which is very sensitive to dosage changes in RTK signaling and downstream components of the PI3K/Akt and Ras/Mapk pathways....
[...]
01 Jan 2000
TL;DR: A different evolutionary origin is suggested of the protocadherin and Flamingo cadherin genes versus the genes encoding desmogleins, desmocollins, classical Cadherins, and atypical cadherins.
Abstract: Cadherins play an important role in specific cell-cell adhesion events. Their expression appears to be tightly regulated during development and each tissue or cell type shows a characteristic pattern of cadherin molecules. Inappropriate regulation of their expression levels or functionality has been observed in human malignancies, in many cases leading to aggravated cancer cell invasion and metastasis. The cadherins form a superfamily with at least six subfamilies, which can be distinguished on the basis of protein domain composition, genomic structure, and phylogenetic analysis of the protein sequences. These subfamilies comprise classical or type-I cadherins, atypical or type-II cadherins, desmocollins, desmogleins, protocadherins and Flamingo cadherins. In addition, several cadherins clearly occupy isolated positions in the cadherin superfamily (cadherin-13, -15, -16, -17, Dachsous, RET, FAT, MEGF1 and most invertebrate cadherins). We suggest a different evolutionary origin of the protocadherin and Flamingo cadherin genes versus the genes encoding desmogleins, desmocollins, classical cadherins, and atypical cadherins. The present phylogenetic analysis may accelerate the functional investigation of the whole cadherin superfamily by allowing focused research of prototype cadherins within each subfamily.
53 citations
TL;DR: A strong propensity to self-association in the RET-TM underlies – and may be required for – dimer formation and oncogenic activation of juxtamembrane cysteine mutants of RET, and explains the close proximity to the plasma membrane of cysteines implicated in MEN2A and MTC syndromes.
Abstract: In patients with medullary thyroid carcinoma (MTC) and type 2A multiple endocrine neoplasia (MEN2A), mutations of cysteine residues in the extracellular juxtamembrane region of the RET receptor tyrosine kinase cause the formation of covalent receptor dimers linked by intermolecular disulfide bonds between unpaired cysteines, followed by oncogenic activation of the RET kinase. The close proximity to the plasma membrane of the affected cysteine residues prompted us to investigate the possible role of the transmembrane (TM) domain of RET (RET-TM) in receptor-receptor interactions underlying dimer formation. Strong self-association of the RET-TM was observed in a biological membrane. Mutagenesis studies indicated the involvement of the evolutionary conserved residues Ser-649 and Ser-653 in RET-TM oligomerization. Unexpectedly, RET-TM interactions were also abrogated in the A639G/A641R double mutant, first identified in a sporadic case of MTC. In agreement with this, no transforming activity could be detected in full-length RET carrying the A639G and A641R mutations, which remained fully responsive to glial cell-line-derived neurotrophic factor (GDNF) stimulation. When introduced in the context of C634R - a cysteine replacement that is prevalent in MEN2A cases - the A639G/A641R mutations significantly reduced dimer formation and transforming activity in this otherwise highly oncogenic RET variant. These data suggest that a strong propensity to self-association in the RET-TM underlies - and may be required for - dimer formation and oncogenic activation of juxtamembrane cysteine mutants of RET, and explains the close proximity to the plasma membrane of cysteine residues implicated in MEN2A and MTC syndromes.
51 citations
Cites methods from "Drosophila RET contains an active t..."
...Full-length RET expression in mammalian cells was determined using C-20 and T-20 anti-RET antibodies from Santa-Cruz, CA, USA, or a monoclonal anti-RET antibody raised against a peptide derived from the RET kinase activation loop as described previously (Abrescia et al., 2005)....
[...]
TL;DR: Despite important differences between the ENS of vertebrates and invertebrates, common features in their programs of neurogenesis, migration, and differentiation suggest that these relatively simple preparations may provide insights into similar developmental processes in more complex systems.
Abstract: Like the vertebrate enteric nervous system (ENS), the insect ENS consists of interconnected ganglia and nerve plexuses that control gut motility. However, the insect ENS lies superficially on the gut musculature, and its component cells can be individually imaged and manipulated within cultured embryos. Enteric neurons and glial precursors arise via epithelial-to-mesenchymal transitions that resemble the generation of neural crest cells and sensory placodes in vertebrates; most cells then migrate extensive distances before differentiating. A balance of proneural and neurogenic genes regulates the morphogenetic programs that produce distinct structures within the insect ENS. In vivo studies have also begun to decipher the mechanisms by which enteric neurons integrate multiple guidance cues to select their pathways. Despite important differences between the ENS of vertebrates and invertebrates, common features in their programs of neurogenesis, migration, and differentiation suggest that these relatively simple preparations may provide insights into similar developmental processes in more complex systems.
49 citations
Cites background from "Drosophila RET contains an active t..."
...More striking is the identification of an authentic homologue of Ret in Drosophila (dRet), containing the same conserved residues required for ligand-mediated activation and signaling in vertebrate Ret proteins (Sugaya et al., 1994; Abrescia et al., 2005)....
[...]
References
More filters
TL;DR: The protein kinase complement of the human genome is catalogued using public and proprietary genomic, complementary DNA, and expressed sequence tag sequences to provide a starting point for comprehensive analysis of protein phosphorylation in normal and disease states and a detailed view of the current state of human genome analysis through a focus on one large gene family.
Abstract: We have catalogued the protein kinase complement of the human genome (the "kinome") using public and proprietary genomic, complementary DNA, and expressed sequence tag (EST) sequences. This provides a starting point for comprehensive analysis of protein phosphorylation in normal and disease states, as well as a detailed view of the current state of human genome analysis through a focus on one large gene family. We identify 518 putative protein kinase genes, of which 71 have not previously been reported or described as kinases, and we extend or correct the protein sequences of 56 more kinases. New genes include members of well-studied families as well as previously unidentified families, some of which are conserved in model organisms. Classification and comparison with model organism kinomes identified orthologous groups and highlighted expansions specific to human and other lineages. We also identified 106 protein kinase pseudogenes. Chromosomal mapping revealed several small clusters of kinase genes and revealed that 244 kinases map to disease loci or cancer amplicons.
7,486 citations
"Drosophila RET contains an active t..." refers background in this paper
...actually correspond to pseudogenes and do not encode enzimatically active kinases [14]....
[...]
...structural motifs which unequivocally identify RET as a unique receptor tyrosine kinase in those species [9,13,14]....
[...]
...Fbgn0011829) is an active tyrosine kinase [14], and may therefore exert functions similar to human RET (herein hRET) with regards to downstream signaling....
[...]
Mark Raymond Adams1, Susan E. Celniker2, Robert A. Holt1, Cheryl A. Evans1 +191 more•Institutions (23)
TL;DR: The nucleotide sequence of nearly all of the approximately 120-megabase euchromatic portion of the Drosophila genome is determined using a whole-genome shotgun sequencing strategy supported by extensive clone-based sequence and a high-quality bacterial artificial chromosome physical map.
Abstract: The fly Drosophila melanogaster is one of the most intensively studied organisms in biology and serves as a model system for the investigation of many developmental and cellular processes common to higher eukaryotes, including humans. We have determined the nucleotide sequence of nearly all of the approximately 120-megabase euchromatic portion of the Drosophila genome using a whole-genome shotgun sequencing strategy supported by extensive clone-based sequence and a high-quality bacterial artificial chromosome physical map. Efforts are under way to close the remaining gaps; however, the sequence is of sufficient accuracy and contiguity to be declared substantially complete and to support an initial analysis of genome structure and preliminary gene annotation and interpretation. The genome encodes approximately 13,600 genes, somewhat fewer than the smaller Caenorhabditis elegans genome, but with comparable functional diversity.
6,180 citations
"Drosophila RET contains an active t..." refers background in this paper
...tified in the Drosophila genome [17,18,29,30], which could be taken to imply that cognate dRET ligands might be ‘‘nonneurotrophic’’ signaling factors....
[...]
TL;DR: It is shown that mice homozygous for a targeted mutation in c-ret develop to term, but die soon after birth, showing renal agenesis or severe dysgenesis, and lacking enteric neurons throughout the digestive tract, indicating an essential component of a signalling pathway required for renal organogenesis and enteric neurogenesis.
Abstract: Receptor tyrosine kinases (RTKs) are cell-surface molecules that transduce signals for cell growth and differentiation. The RTK encoded by the c-ret proto-oncogene is rearranged and constitutively activated in a large proportion of thyroid papillary carcinomas, and germ-line point mutations in c-ret seem to be responsible for the dominantly inherited cancer syndromes multiple endocrine neoplasia (MEN) types 2A and B. The gene is expressed in the developing central and peripheral nervous systems (sensory, autonomic and enteric ganglia) and the excretory system (Wolffian duct and ureteric bud epithelium) of mice, indicating that it may play a role in normal development. Here we show that mice homozygous for a targeted mutation in c-ret develop to term, but die soon after birth, showing renal agenesis or severe dysgenesis, and lacking enteric neurons throughout the digestive tract. Ret is thus an essential component of a signalling pathway required for renal organogenesis and enteric neurogenesis.
1,580 citations
Howard Hughes Medical Institute1, Celera Corporation2, University of California, Berkeley3, Harvard University4, University of Pennsylvania5, Wellcome Trust6, Stanford University7, Fred Hutchinson Cancer Research Center8, National Institutes of Health9, Lawrence Berkeley National Laboratory10, University of Leeds11, University of California, San Diego12, California Institute of Technology13, Massachusetts Institute of Technology14, BC Cancer Research Centre15, University of Maryland, Baltimore16, Centre national de la recherche scientifique17, University of California, San Francisco18, Columbia University19, Baylor College of Medicine20
TL;DR: The fly has orthologs to 177 of the 289 human disease genes examined and provides the foundation for rapid analysis of some of the basic processes involved in human disease.
Abstract: A comparative analysis of the genomes of Drosophila melanogaster, Caenorhabditis elegans, and Saccharomyces cerevisiae-and the proteins they are predicted to encode-was undertaken in the context of cellular, developmental, and evolutionary processes. The nonredundant protein sets of flies and worms are similar in size and are only twice that of yeast, but different gene families are expanded in each genome, and the multidomain proteins and signaling pathways of the fly and worm are far more complex than those of yeast. The fly has orthologs to 177 of the 289 human disease genes examined and provides the foundation for rapid analysis of some of the basic processes involved in human disease.
1,563 citations
TL;DR: In this paper, the expression cloning and characterization of GDNFR-α, a novel glycosylphosphatidylinositol-linked cell surface receptor for glial cell line-derived neurotrophic factor (GDNF), was reported.
1,164 citations