scholarly journals New genomic data and analyses challenge the traditional vision of animal epithelium evolution

2017 ◽  
Author(s):  
Hassiba Belahbib ◽  
Emmanuelle Renard ◽  
Sébastien Santini ◽  
Cyril Jourda ◽  
Jean-Michel Claverie ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cell Polarity ◽  
Protein Complexes ◽  
Genomic Data ◽  
Genes Encoding ◽  
Interaction Domains ◽  
Unexpected Findings ◽  
Crumbs Complex ◽  
Adhesive Type ◽  
E Cadherin

AbstractThe emergence of epithelia was the foundation of metazoan expansion. To investigate the early evolution of animal epithelia, we sequenced the genome and transcriptomes of two new sponge species to characterize epithelial markers such as the E-cadherin complex and the polarity complexes for all classes (Calcarea, Demospongiae, Hexactinellida, Homoscleromorpha) of sponges (phylum Porifera) and compare them with their homologs in Placozoa and in Ctenophora. We found that Placozoa and most sponges possess orthologs of all essential genes encoding proteins characteristic of bilaterian epithelial cells, as well as their conserved interaction domains. In stark contrast, we found that ctenophores lack several major polarity complex components such as the Crumbs complex and Scribble. Furthermore, the E-cadherin ctenophore ortholog exhibits a divergent cytoplasmic domain making it unlikely to interact with its canonical cytoplasmic partners. These unexpected findings challenge the current evolutionary paradigm on the emergence of epithelia.SIGNIFICANT STATEMENTEpithelial tissues are a hallmark of metazoans deeply linked to the evolution of the complex morphogenesis processes characterizing their development. However, studies on the epithelial features of non-bilaterians are still sparse and it remains unclear whether the last common metazoan ancestor possessed a fully functional epithelial toolkit or if it was acquired later during metazoan evolution. In this work, we demonstrate that if sponges have a well conserved and functionally predicted epithelial toolkit, Ctenophores have either divergent adhesion complexes or lack essential polarity complexes. Altogether, our results raise a doubt on the homology of protein complexes and structures involved in cell polarity and adhesive type junctions between Ctenophora and Bilateria epithelia.

scholarly journals Polycystin-1 and Gα12 regulate the cleavage of E-cadherin in kidney epithelial cells

2015 ◽  
Vol 47 (2) ◽  
pp. 24-32 ◽  
Author(s):  
Jen X. Xu ◽  
Tzong-Shi Lu ◽  
Suyan Li ◽  
Yong Wu ◽  
Lai Ding ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Signaling Pathway ◽  
Cell Polarity ◽  
Mdck Cells ◽  
Adherens Junction ◽  
Renal Epithelial Cells ◽  
Extracellular Milieu ◽  
Kidney Epithelial Cells ◽  
Autosomal Dominant Polycystic Kidney ◽  
E Cadherin

Interaction of polycystin-1 (PC1) and Gα12 is important for development of kidney cysts in autosomal dominant polycystic kidney disease (ADPKD). The integrity of cell polarity and cell-cell adhesions (mainly E-cadherin-mediated adherens junction) is altered in the renal epithelial cells of ADPKD. However, the key signaling pathway for this alteration is not fully understood. Madin-Darby canine kidney (MDCK) cells maintain the normal integrity of epithelial cell polarity and adherens junctions. Here, we found that deletion of Pkd1 increased activation of Gα12, which then promoted the cystogenesis of MDCK cells. The morphology of these cells was altered after the activation of Gα12. By using liquid chromatography-mass spectrometry, we found several proteins that could be related this change in the extracellular milieu. E-cadherin was one of the most abundant peptides after active Gα12 was induced. Gα12 activation or Pkd1 deletion increased the shedding of E-cadherin, which was mediated via increased ADAM10 activity. The increased shedding of E-cadherin was blocked by knockdown of ADAM10 or specific ADAM10 inhibitor GI254023X. Pkd1 deletion or Gα12 activation also changed the distribution of E-cadherin in kidney epithelial cells and caused β-catenin to shift from cell membrane to nucleus. Finally, ADAM10 inhibitor, GI254023 X, blocked the cystogenesis induced by PC1 knockdown or Gα12 activation in renal epithelial cells. Our results demonstrate that the E-cadherin/β-catenin signaling pathway is regulated by PC1 and Gα12 via ADAM10. Specific inhibition of this pathway, especially ADAM10 activity, could be a novel therapeutic regimen for ADPKD.

scholarly journals Frizzled3 inhibits Vangl2-Prickle3 association to establish planar cell polarity in the vertebrate neural plate

2021 ◽  
Author(s):  
Ilya Chuykin ◽  
Keiji Itoh ◽  
Kyeongmi Kim ◽  
Sergei Y. Sokol
Keyword(s):  
Epithelial Cells ◽  
Complex Formation ◽  
Cell Polarity ◽  
Planar Cell Polarity ◽  
Protein Complexes ◽  
Neural Plate ◽  
Van Gogh

The orientation of epithelial cells in the plane of the tissue, known as planar cell polarity (PCP), is regulated by interactions of asymmetrically localized PCP protein complexes. In the Xenopus neural plate, Van Gogh-like2 (Vangl2) and Prickle3 (Pk3) proteins form a complex at the anterior cell boundaries, but how this complex is regulated in vivo remains largely unknown. Here we use proximity biotinylation and crosslinking approaches to show that Vangl2-Pk3 association is inhibited by Frizzled3 (Fz3), a core PCP protein that is specifically expressed in the neuroectoderm and is essential for the establishment of PCP in this tissue. This inhibition required Fz3-dependent Vangl2 phosphorylaton. Consistent with our observations, the complex of Pk3 with nonphosphorylatable Vangl2 did not polarize in the neural plate. These findings provide evidence for in vivo regulation of Vangl2-Pk3 complex formation and localization by a Frizzled receptor.

Histopathological analysis of renal cystic epithelia in the Pkd2WS25/- mouse model of ADPKD

2003 ◽  
Vol 285 (5) ◽  
pp. F870-F880 ◽  
Author(s):  
R. Brent Thomson ◽  
SueAnn Mentone ◽  
Robert Kim ◽  
Karen Earle ◽  
Eric Delpire ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Mouse Model ◽  
Cell Polarity ◽  
Late Stage ◽  
Histopathological Analysis ◽  
Cell Dedifferentiation ◽  
Cyst Cell ◽  
Autosomal Dominant Polycystic Kidney ◽  
E Cadherin

It has been proposed that autosomal dominant polycystic kidney disease (ADPKD)affected renal epithelial cells undergo a phenotypic transition from a highly differentiated absorptive state to a much less differentiated secretory state during cystogenesis and that this transition is accompanied by loss of epithelial cell polarity and mistargeting of specific membrane proteins. We conducted a detailed evaluation of this hypothesis in the Pkd2 WS25/- mouse model of ADPKD. Ultrastructural analysis of Pkd2 WS25/- cysts by electron microscopy confirmed that cystic epithelial cells progressively dedifferentiate with cyst enlargement. Immunocytochemical analysis of both early- and late-stage cysts with antibodies directed against Na+-K+-ATPase, Ksp-cadherin, and E-cadherin failed to detect evidence of altered cyst cell polarity. Na+-K+-ATPase and Ksp-cadherin were expressed exclusively on the basolateral membranes (BLM) of epithelial cells in all early cysts. Expression levels of both Na+-K+-ATPase and Ksp-cadherin decreased progressively with the degree of cyst cell dedifferentiation, but neither protein was ever mislocalized. Highly dedifferentiated cysts did not express immunodetectable levels of either Na+-K+-ATPase or Ksp-cadherin. E-cadherin was expressed prominently on the BLM of all cysts. Cysts were subsequently stained with an antibody directed against the secretory isoform of the Na+-K+-Cl- cotransporter NKCC1. NKCC1 expression was detected on the BLM of advanced cysts only. Our data are consistent with a model of progressive cystic epithelial cell dedifferentiation in which fluid accumulation in late-stage cysts is mediated by transepithelial secretion of chloride rather than secretion of sodium by apical Na+-K+-ATPase.

scholarly journals Frizzled3 inhibits Vangl2-Prickle3 association to establish planar cell polarity in the vertebrate neural plate

2021 ◽  
Author(s):  
Ilya Chuykin ◽  
Kyeongmi Kim ◽  
Sergei Sokol
Keyword(s):  
Epithelial Cells ◽  
Complex Formation ◽  
Cell Polarity ◽  
Planar Cell Polarity ◽  
Protein Complexes ◽  
Neural Plate ◽  
Van Gogh

The orientation of epithelial cells in the plane of the tissue, known as planar cell polarity (PCP), is regulated by interactions of asymmetrically localized PCP protein complexes. In the Xenopus neural plate, Van Gogh-like2 (Vangl2) and Prickle3 (Pk3) proteins form a complex at the anterior cell boundaries, but how this complex is regulated in vivo remains largely unknown. Here we show that Vangl2-Pk3 association is inhibited by Frizzled3 (Fz3), a core PCP protein that is specifically expressed in the neuroectoderm and is essential for the establishment of PCP in this tissue. Proximity biotinylation and crosslinking studies revealed that the Vangl2-Pk3 interaction is suppressed by overexpressed Fz3, but enhanced in Fz3 morphants. In addition, Fz3 induced Vangl2 phosphorylation on T76 and T78, and this phosphorylation was required for Fz3-mediated inhibition of Vangl2-Pk3 complex formation. Consistent with this observation, the complex of Pk3 with nonphosphorylatable Vangl2 was not polarized in the neural plate. These findings provide evidence for in vivo regulation of Vangl2-Pk3 complex formation and localization by a Frizzled receptor.

Protein Interaction Domains and Post-Translational Modifications: Structural Features and Drug Discovery Applications

2020 ◽  
Vol 27 (37) ◽  
pp. 6306-6355 ◽  
Author(s):  
Marian Vincenzi ◽  
Flavia Anna Mercurio ◽  
Marilisa Leone
Keyword(s):  
Drug Discovery ◽  
Protein Interaction ◽  
Protein Interactions ◽  
Structural Information ◽  
Protein Complexes ◽  
Structural Features ◽  
Protein Protein Interactions ◽  
Modular Architecture ◽  
Post Translational Modifications ◽  
Interaction Domains

Background:: Many pathways regarding healthy cells and/or linked to diseases onset and progression depend on large assemblies including multi-protein complexes. Protein-protein interactions may occur through a vast array of modules known as protein interaction domains (PIDs). Objective:: This review concerns with PIDs recognizing post-translationally modified peptide sequences and intends to provide the scientific community with state of art knowledge on their 3D structures, binding topologies and potential applications in the drug discovery field. Method:: Several databases, such as the Pfam (Protein family), the SMART (Simple Modular Architecture Research Tool) and the PDB (Protein Data Bank), were searched to look for different domain families and gain structural information on protein complexes in which particular PIDs are involved. Recent literature on PIDs and related drug discovery campaigns was retrieved through Pubmed and analyzed. Results and Conclusion:: PIDs are rather versatile as concerning their binding preferences. Many of them recognize specifically only determined amino acid stretches with post-translational modifications, a few others are able to interact with several post-translationally modified sequences or with unmodified ones. Many PIDs can be linked to different diseases including cancer. The tremendous amount of available structural data led to the structure-based design of several molecules targeting protein-protein interactions mediated by PIDs, including peptides, peptidomimetics and small compounds. More studies are needed to fully role out, among different families, PIDs that can be considered reliable therapeutic targets, however, attacking PIDs rather than catalytic domains of a particular protein may represent a route to obtain selective inhibitors.

scholarly journals Protein complex formation in methionine chain-elongation and leucine biosynthesis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Li-Qun Chen ◽  
Shweta Chhajed ◽  
Tong Zhang ◽  
Joseph M. Collins ◽  
Qiuying Pang ◽  
...  
Keyword(s):  
Protein Complexes ◽  
Complete Characterization ◽  
Bimolecular Fluorescence Complementation ◽  
Chain Elongation ◽  
Substrate Channeling ◽  
Leucine Biosynthesis ◽  
Protein Complex Formation ◽  
Genes Encoding ◽  
Isopropylmalate Dehydrogenase

AbstractDuring the past two decades, glucosinolate (GLS) metabolic pathways have been under extensive studies because of the importance of the specialized metabolites in plant defense against herbivores and pathogens. The studies have led to a nearly complete characterization of biosynthetic genes in the reference plant Arabidopsis thaliana. Before methionine incorporation into the core structure of aliphatic GLS, it undergoes chain-elongation through an iterative three-step process recruited from leucine biosynthesis. Although enzymes catalyzing each step of the reaction have been characterized, the regulatory mode is largely unknown. In this study, using three independent approaches, yeast two-hybrid (Y2H), coimmunoprecipitation (Co-IP) and bimolecular fluorescence complementation (BiFC), we uncovered the presence of protein complexes consisting of isopropylmalate isomerase (IPMI) and isopropylmalate dehydrogenase (IPMDH). In addition, simultaneous decreases in both IPMI and IPMDH activities in a leuc:ipmdh1 double mutants resulted in aggregated changes of GLS profiles compared to either leuc or ipmdh1 single mutants. Although the biological importance of the formation of IPMI and IPMDH protein complexes has not been documented in any organisms, these complexes may represent a new regulatory mechanism of substrate channeling in GLS and/or leucine biosynthesis. Since genes encoding the two enzymes are widely distributed in eukaryotic and prokaryotic genomes, such complexes may have universal significance in the regulation of leucine biosynthesis.

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