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A role for caveolin-1 in desmoglein binding and desmosome dynamics

Oncogene volume 31, pages 1636–1648 (2012)Cite this article

Abstract

Desmoglein-2 (Dsg2) is a desmosomal cadherin that is aberrantly expressed in human skin carcinomas. In addition to its well-known role in mediating intercellular desmosomal adhesion, Dsg2 regulates mitogenic signaling that may promote cancer development and progression. However, the mechanisms by which Dsg2 activates these signaling pathways and the relative contribution of its signaling and adhesion functions in tumor progression are poorly understood. In this study we show that Dsg2 associates with caveolin-1 (Cav-1), the major protein of specialized membrane microdomains called caveolae, which functions in both membrane protein turnover and intracellular signaling. Sequence analysis revealed that Dsg2 contains a putative Cav-1-binding motif. A permeable competing peptide resembling the Cav-1 scaffolding domain bound to Dsg2, disrupted normal Dsg2 staining and interfered with the integrity of epithelial sheets in vitro. Additionally, we observed that Dsg2 is proteolytically processed; resulting in a 95-kDa ectodomain shed product and a 65-kDa membrane-spanning fragment, the latter of which localizes to lipid rafts along with full-length Dsg2. Disruption of lipid rafts shifted Dsg2 to the non-raft fractions, leading to the accumulation of these proteins. Interestingly, Dsg2 proteolytic products are elevated in vivo in skin tumors from transgenic mice overexpressing Dsg2. Collectively, these data are consistent with the possibility that accumulation of truncated Dsg2 protein interferes with desmosome assembly and/or maintenance to disrupt cell–cell adhesion. Furthermore, the association of Dsg2 with Cav-1 may provide a mechanism for regulating mitogenic signaling and modulating the cell-surface presentation of an important adhesion molecule, both of which could contribute to malignant transformation and tumor progression.

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Acknowledgements

We thank Dr Abhilasha Gupta for critically reading the paper and insightful discussions. This work was supported by grants from the National Institutes of Health to M Mahoney (R01 AR47938), J Wahl (R01 DE01905) and K Green (R01 CA122151).

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Authors and Affiliations

  1. Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA, USA

    D Brennan, A Dowling, W Medhat & M G Mahoney

  2. Department of Dermatology, University of Turku and Turku University Hospital, Turku, Finland

    S Peltonen

  3. Departments of Pathology and Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA

    K J Green

  4. Department of Oral Biology, University of Nebraska Medical Center, Lincoln, NE, USA

    J K Wahl III

  5. Scleroderma Research Centre, Leeds Institute of Molecular Medicine, LMBU, University of Leeds, Leeds, UK

    F Del Galdo

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  1. D Brennan
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Correspondence to M G Mahoney.

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Brennan, D., Peltonen, S., Dowling, A. et al. A role for caveolin-1 in desmoglein binding and desmosome dynamics. Oncogene 31, 1636–1648 (2012). https://doi.org/10.1038/onc.2011.346

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