scholarly journals PARP12-catalyzed mono-ADP-ribosylation of Golgin-97 controls the transport of E-cadherin

2020 ◽  
Author(s):  
Giovanna Grimaldi ◽  
Laura Schembri ◽  
Matteo Lo Monte ◽  
Daniela Spano ◽  
Rosaria Di Martino ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cell Biology ◽  
Epithelial To Mesenchymal Transition ◽  
Specific Substrate ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Mesenchymal Transition ◽  
Adp Ribosylation ◽  
Golgi Network ◽  
E Cadherin

AbstractADP-ribosylation is a post-translational modification involved in physiological and pathological events catalyzed by Poly-ADP-Ribosyl-Polymerase (PARP) enzymes. Substrates of this reaction have been identified by mass-spectrometry, but the definition of PARPs-regulated cellular functions remains scarce. Here, we have analyzed the control of intracellular membrane traffic by the mono-ADP-ribosyl-transferase PARP12, motivated by its localization at the trans-Golgi network. By using bioinformatics, mutagenesis and cell biology approaches we identified Golgin-97, a protein regulating exocytosis, as a PARP12-specific substrate. Mono-ADP-ribosylation of Golgin-97 residues E558-E559-E565 is required for supporting traffic from the trans-Golgi network to the plasma membrane. This step is halted when PARP12 is deleted or when the Golgin-97 ADP-ribosylation-defective mutant is expressed. Under these conditions E-cadherin, whose transport is controlled by Golgin-97, does not reach the plasma membrane but accumulates in a trans-Golgi proximal compartment. Thus, we demonstrate that the ADP-ribosylation of Golgin-97 is required for E-cadherin exocytosis and thus this event may regulate the sorting of exocytic carriers as well as epithelial-to-mesenchymal transition.

scholarly journals Molecular regulation of Snai2 in development and disease

2019 ◽  
Vol 132 (23) ◽  
Author(s):  
Wenhui Zhou ◽  
Kayla M. Gross ◽  
Charlotte Kuperwasser
Keyword(s):  
Transcription Factor ◽  
Cell Biology ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Zinc Finger Protein ◽  
Main Role ◽  
Biological Processes ◽  
Developmental Defects ◽  
Mesenchymal Transition ◽  
Damage Repair

ABSTRACT The transcription factor Snai2, encoded by the SNAI2 gene, is an evolutionarily conserved C2H2 zinc finger protein that orchestrates biological processes critical to tissue development and tumorigenesis. Initially characterized as a prototypical epithelial-to-mesenchymal transition (EMT) transcription factor, Snai2 has been shown more recently to participate in a wider variety of biological processes, including tumor metastasis, stem and/or progenitor cell biology, cellular differentiation, vascular remodeling and DNA damage repair. The main role of Snai2 in controlling such processes involves facilitating the epigenetic regulation of transcriptional programs, and, as such, its dysregulation manifests in developmental defects, disruption of tissue homeostasis, and other disease conditions. Here, we discuss our current understanding of the molecular mechanisms regulating Snai2 expression, abundance and activity. In addition, we outline how these mechanisms contribute to disease phenotypes or how they may impact rational therapeutic targeting of Snai2 dysregulation in human disease.

scholarly journals Lessons to Learn for Adequate Targeted Therapy Development in Metastatic Colorectal Cancer Patients

2021 ◽  
Vol 22 (9) ◽  
pp. 5019
Author(s):  
Helena Oliveres ◽  
David Pesántez ◽  
Joan Maurel
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Cancer Patients ◽  
Tyrosine Kinases ◽  
Epithelial To Mesenchymal Transition ◽  
Acquired Resistance ◽  
Post Translational Modification ◽  
Mesenchymal Transition ◽  
Igf1r Signaling ◽  
Colorectal Cancer Patients

Insulin-like growth factor 1 receptor (IGF1R) is a receptor tyrosine kinase that regulates cell growth and proliferation. Upregulation of the IGF1R pathway constitutes a common paradigm shared with other receptor tyrosine kinases such as EGFR, HER2, and MET in different cancer types, including colon cancer. The main IGF1R signaling pathways are PI3K-AKT and MAPK-MEK. However, different processes, such as post-translational modification (SUMOylation), epithelial-to-mesenchymal transition (EMT), and microenvironment complexity, can also contribute to intrinsic and acquired resistance. Here, we discuss new strategies for adequate drug development in metastatic colorectal cancer patients.

Metformin mediated reversal of epithelial to mesenchymal transition is triggered by epigenetic changes in E-cadherin promoter

2016 ◽  
Vol 94 (12) ◽  
pp. 1397-1409 ◽  
Author(s):  
Poulomi Banerjee ◽  
Harshini Surendran ◽  
Debabani Roy Chowdhury ◽  
Karthik Prabhakar ◽  
Rajarshi Pal
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Epigenetic Changes ◽  
Mesenchymal Transition ◽  
E Cadherin

PI(4,5)P2 Clustering and Its Impact on Biological Functions

2021 ◽  
Vol 90 (1) ◽  
Author(s):  
Yi Wen ◽  
Volker M. Vogt ◽  
Gerald W. Feigenson
Keyword(s):  
Plasma Membrane ◽  
Cell Biology ◽  
Cellular Proteins ◽  
Annual Review ◽  
Publication Date ◽  
Biological Functions ◽  
Cellular Functions ◽  
Dynamic Distribution ◽  
Multivalent Cation ◽  
Lipid Environment

Located at the inner leaflet of the plasma membrane, phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] comprises only 1–2 mol% of total PM lipids. With its synthesis and turnover both spatially and temporally regulated, PI(4,5)P2 recruits and interacts with hundreds of cellular proteins to support a broad spectrum of cellular functions. Several factors contribute to the versatile and dynamic distribution of PI(4,5)P2 in membranes. Physiological multivalent cations such as Ca2+ and Mg2+ can bridge between PI(4,5)P2 headgroups, forming nanoscopic PI(4,5)P2–cation clusters. The distinct lipid environment surrounding PI(4,5)P2 affects the degree of PI(4,5)P2 clustering. In addition, diverse cellular proteins interacting with PI(4,5)P2 can further regulate PI(4,5)P2 lateral distribution and accessibility. This review summarizes the current understanding of PI(4,5)P2 behavior in both cells and model membranes, with emphasis on both multivalent cation– and protein-induced PI(4,5)P2 clustering. Understanding the nature of spatially separated pools of PI(4,5)P2 is fundamental to cell biology. Expected final online publication date for the Annual Review of Biochemistry, Volume 90 is June 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Epithelial-to-mesenchymal transition in cyst lining epithelial cells in an orthologous PCK rat model of autosomal-recessive polycystic kidney disease

2011 ◽  
Vol 300 (2) ◽  
pp. F511-F520 ◽  
Author(s):  
Hiroko Togawa ◽  
Koichi Nakanishi ◽  
Hironobu Mukaiyama ◽  
Taketsugu Hama ◽  
Yuko Shima ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Epithelial Cells ◽  
Polycystic Kidney Disease ◽  
Autosomal Recessive ◽  
Epithelial To Mesenchymal Transition ◽  
Cell Contact ◽  
Polycystic Kidney ◽  
Mesenchymal Transition ◽  
Cyst Lining ◽  
E Cadherin

In polycystic kidney disease (PKD), cyst lining cells show polarity abnormalities. Recent studies have demonstrated loss of cell contact in cyst cells, suggesting induction of epithelial-to-mesenchymal transition (EMT). Recently, EMT has been implicated in the pathogenesis of PKD. To explore further evidence of EMT in PKD, we examined age- and segment-specific expression of adhesion molecules and mesenchymal markers in PCK rats, an orthologous model of human autosomal-recessive PKD. Kidneys from 5 male PCK and 5 control rats each at 0 days, 1, 3, 10, and 14 wk, and 4 mo of age were serially sectioned and stained with segment-specific markers and antibodies against E-cadherin, Snail1, β-catenin, and N-cadherin. mRNAs for E-cadherin and Snail1 were quantified by real-time PCR. Vimentin, fibronectin, and α-smooth muscle actin (α-SMA) expressions were assessed as mesenchymal markers. E-cadherin expression pattern was correlated with the disease pathology in that tubule segments showing the highest expression in control had much severer cyst formation in PCK rats. In PCK rats, E-cadherin and β-catenin in cystic tubules was attenuated and localized to lateral areas of cell-cell contact, whereas nuclear expression of Snail1 increased in parallel with cyst enlargement. Some epithelial cells in large cysts derived from these segments, especially in adjacent fibrotic areas, showed positive immunoreactivity for vimentin and fibronectin. In conclusion, these findings suggest that epithelial cells in cysts acquire mesenchymal features in response to cyst enlargement and participate in progressive renal fibrosis. Our study clarified the nephron segment-specific cyst profile related to EMT in PCK rats. EMT may play a key role in polycystic kidney disease.

scholarly journals Hepatitis C virus depends on E-cadherin as an entry factor and regulates its expression in epithelial-to-mesenchymal transition

2016 ◽  
Vol 113 (27) ◽  
pp. 7620-7625 ◽  
Author(s):  
Qisheng Li ◽  
Catherine Sodroski ◽  
Brianna Lowey ◽  
Cameron J. Schweitzer ◽  
Helen Cha ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Cell Surface ◽  
Viral Entry ◽  
Epithelial To Mesenchymal Transition ◽  
Hcv Infection ◽  
Hcv Rna ◽  
Entry Site ◽  
Mesenchymal Transition ◽  
E Cadherin

Hepatitis C virus (HCV) enters the host cell through interactions with a cascade of cellular factors. Although significant progress has been made in understanding HCV entry, the precise mechanisms by which HCV exploits the receptor complex and host machinery to enter the cell remain unclear. This intricate process of viral entry likely depends on additional yet-to-be-defined cellular molecules. Recently, by applying integrative functional genomics approaches, we identified and interrogated distinct sets of host dependencies in the complete HCV life cycle. Viral entry assays using HCV pseudoparticles (HCVpps) of various genotypes uncovered multiple previously unappreciated host factors, including E-cadherin, that mediate HCV entry. E-cadherin silencing significantly inhibited HCV infection in Huh7.5.1 cells, HepG2/miR122/CD81 cells, and primary human hepatocytes at a postbinding entry step. Knockdown of E-cadherin, however, had no effect on HCV RNA replication or internal ribosomal entry site (IRES)-mediated translation. In addition, an E-cadherin monoclonal antibody effectively blocked HCV entry and infection in hepatocytes. Mechanistic studies demonstrated that E-cadherin is closely associated with claudin-1 (CLDN1) and occludin (OCLN) on the cell membrane. Depletion of E-cadherin drastically diminished the cell-surface distribution of these two tight junction proteins in various hepatic cell lines, indicating that E-cadherin plays an important regulatory role in CLDN1/OCLN localization on the cell surface. Furthermore, loss of E-cadherin expression in hepatocytes is associated with HCV-induced epithelial-to-mesenchymal transition (EMT), providing an important link between HCV infection and liver cancer. Our data indicate that a dynamic interplay among E-cadherin, tight junctions, and EMT exists and mediates an important function in HCV entry.

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