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Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/10836

Title: CADM1 isoforms differentially regulate human mast cell survival and homotypic adhesion
Authors: Moiseeva, Elena P.
Leyland, Mark L.
Bradding, Peter
Issue Date: 22-Mar-2012
Publisher: Springer Verlag
Citation: Cellular and Molecular Life Sciences, 2012, 69 (16), pp. 2751-2764
Abstract: Cell adhesion molecule 1 (CADM1), expressed by human lung mast cells (HLMCs), mediates their adhesion to airway smooth muscle (ASM), and contributes to ASM-dependent HLMC proliferation and survival. CADM1 is expressed in alternatively spliced isoforms, but those present in HLMCs and their function are not known. We cloned three functional and one cryptic non-functional isoform with alternative splicing between exons 7/11 and 1/2, respectively, from HLMCs and human MC lines (HMC-1 and LAD2). Differentiated HLMCs and LAD2 cells expressed the functional isoform SP4 containing exons 7/8/11 (*80% of clones), as well as SP1 (exons 7/8/ 9/11) and a novel SP6 (exons 7/8/9/10/11). In contrast, immature HMC-1 cells expressed only functional SP4. SP4 overexpression in HMC-1 cells and HLMCs augmented homotypic adhesion to a greater extent than SP1 in various conditions. In contrast, CADM1 downregulation abolished homotypic adhesion, indicating that CADM1 is the sole receptor mediating mast cell aggregation. CADM1-mediated adhesion was enhanced by the presence of cell survival factors. SP1 overexpression in HMC-1 cells compromised survival compared to SP4 overexpression or control. CADM1 downregulation resulted in reduced viability and decreased expression of the pro-survival protein Mcl-1L, but not Blc-2 or Bcl-XL, and increased caspase-3/7 activity in both HMC-1 cells and HLMCs. This coincided with decreased basal Kit levels in HLMCs. In summary, human MCs express multiple CADM1 isoforms which exhibit differential regulation of survival and homotypic adhesion. The most highly expressed SP4 isoform is likely to contribute to MC aggregation and longevity in mastocytosis, and augment the pathophysiology of allergic diseases.
DOI Link: 10.1007/s00018-012-0948-y
ISSN: 1420-682X
eISSN: 1420-9071
Links: http://link.springer.com/article/10.1007%2Fs0(...)
http://hdl.handle.net/2381/10836
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © The Author(s) 2012. This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
Appears in Collections:Published Articles, Dept. of Infection, Immunity and Inflammation

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