Somatic transmembrane domain mutations of a cell adhesion molecule, CADM1, cause primary aldosteronism by preventing gap junction communication between adrenocortical cells

2019 ◽  
Author(s):  
Xilin Wu ◽  
Sumedha Garg ◽  
Claudia Cabrera ◽  
Elena Azizan ◽  
Junhua Zhou ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Gap Junction ◽  
Adhesion Molecule ◽  
Primary Aldosteronism ◽  
Cell Adhesion Molecule ◽  
Transmembrane Domain ◽  
Adrenocortical Cells ◽  
Gap Junction Communication ◽  
A Cell

scholarly journals OR34-02 Somatic Transmembrane Domain Mutations of a Cell Adhesion Molecule, CADM1, Cause Primary Aldosteronism by Preventing Gap Junction Communication Between Adrenocortical Cells

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Xilin Wu ◽  
Sumedha Garg ◽  
Claudia P Cabrera ◽  
Elena Azizan ◽  
Junhua Zhou ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Primary Aldosteronism ◽  
Cell Adhesion Molecule ◽  
Transmembrane Domain ◽  
Fold Increase ◽  
Protein Modelling ◽  
Dye Transfer ◽  
Aldosterone Secretion ◽  
H295r Cells

Abstract Primary Aldosteronism (PA) is the commonest curable cause of hypertension. Whole exome sequencing (WES) in 2011 and 2013 identified common somatic mutations in genes regulating membrane polarisation in 60–80% of aldosterone-producing adenomas (APA). We undertook WES on 39 consecutive APAs in search of further variants. 1 APA revealed a somatic mutation (Val380Asp) within the single transmembrane domain of Cell Adhesion Molecule 1 (CADM1). An adjacent mutation (Gly379Asp) was discovered on WES from a PA patient in Munich. Both short and long isoforms (442 & 453 residues) of wild-type (WT) and both mutant CADM1 genes were cloned into lentivirus vectors and each transduced into adrenocortical (H295R) cells to assess its effect on aldosterone secretion and other parameters. Previous studies in pancreatic islet cells suggested a role of CADM1 in regulating gap junction (GJ) communication. To assess this we microinjected single WT or mutant H295R cells with the GJ permeable dye calceinAM and counted the dye-positive cells after 1 hour. The effect of inhibiting or silencing GJs in H295R cells using peptide gap27 or a Dharmacon smartpool was assessed. H295R cells were also co-transfected with WT or mutant CADM1 and the GJ protein CX43, tagged with the mApple fluorophore. These were mixed with cells transfected with CX43-Venus, allowing confocal visualisation of GJ formation. Protein modelling was undertaken to determine whether Asp in the intramembranous domain changes angulation of CADM1. All mutant isoforms had consistently different effects, shown as a range compared to WT. Cells transduced with mutant CADM1 showed 3-6-fold increase in aldosterone secretion (p<0.01) and 10-20-fold increase in CYP11B2 expression (p<0.001) compared to WT. Dye transfer assays showed paucity of dye transfer between neighbouring mutant CADM1 cells, while calcein passed easily through GJs in WT cells. CX43 inhibition increased aldosterone secretion 2-fold (p<0.01), and CYP11B2 expression 3 to 8-fold (<0.001). Knock-down of GJ proteins increased aldosterone secretion 1.5-fold (p<0.01) and CYP11B2 expression 1.7-fold (p<0.001). Protein modelling showed mutations to increase the angle of ectodomains to cell membrane, from 49o in WT cells, to 62o and 90o in Gly379Asp and Val380Asp respectively; increasing inter-cell distance from 21.2nm to 24.7 and 27.9nm. Mixing of Venus and mApple-tagged CX43 transfected cells showed fewer intact GJ channels in cells co-transfected with mutant compared to WT CADM1 [mutant 42/291 (14.4%) VS WT 68/212 (32.1%) p<0.001]. The CADM1 mutations shows the importance of membrane proteins in aldosterone regulation to extend beyond ion channels and transporters. A key role may be to bring opposing CX43 hemichannels close enough to form GJ channels, permitting the oscillating Ca2+ currents which regulate aldosterone in intact adrenal slices.

Function and Histopathology of a Cell Adhesion Molecule TSLC1 in Cancer

2011 ◽  
Vol 29 (2) ◽  
pp. 107-112 ◽  
Author(s):  
Qi-Lian Liang ◽  
Guo-Qiang Chen ◽  
Zhou-Yu Li ◽  
Bi-Rong Wang
Keyword(s):  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
A Cell

Design of a Calcium-Binding Protein with Desired Structure in a Cell Adhesion Molecule

2005 ◽  
Vol 127 (7) ◽  
pp. 2085-2093 ◽  
Author(s):  
Wei Yang ◽  
Anna L. Wilkins ◽  
Yiming Ye ◽  
Zhi-ren Liu ◽  
Shun-yi Li ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Calcium Binding ◽  
Cell Adhesion Molecule ◽  
Binding Protein ◽  
Calcium Binding Protein ◽  
A Cell

scholarly journals Potential role of SC1, a cell adhesion molecule, in mammary gland tumors

2008 ◽  
Author(s):  
Kenji Hagimori ◽  
Hidenori Kato ◽  
Keiko Fukuda ◽  
Masaharu Kikuta ◽  
Yasuhiro Tsukamoto ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Mammary Gland ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Potential Role ◽  
Mammary Gland Tumors ◽  
A Cell

scholarly journals EpCAM as Modulator of Tissue Plasticity

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2128
Author(s):  
François Fagotto
Keyword(s):  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Cancer Prognosis ◽  
Potential Significance ◽  
Cell Adhesion And Migration ◽  
A Cell ◽  
Embryonic Morphogenesis ◽  
And Migration ◽  
Signalling Cascade

The Epithelial Cell Adhesion Molecule or EpCAM is a well-known marker highly expressed in carcinomas and showing a strong correlation with poor cancer prognosis. While its name relates to its proposed function as a cell adhesion molecule, EpCAM has been shown to have various signalling functions. In particular, it has been identified as an important positive regulator of cell adhesion and migration, playing an essential role in embryonic morphogenesis as well as intestinal homeostasis. This activity is not due to its putative adhesive function, but rather to its ability to repress myosin contractility by impinging on a PKC signalling cascade. This mechanism confers EpCAM the unique property of favouring tissue plasticity. I review here the currently available data, comment on possible connections with other properties of EpCAM, and discuss the potential significance in the context of cancer invasion.

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