Folliculin, the Product of the Birt-Hogg-Dube Tumor Suppressor Gene, Interacts with the Adherens Junction Protein p0071 to Regulate Cell-Cell Adhesion

PLoS One

Venkatesh Hariharan¹  Hayden Huang¹  Thomas N. Darling²  Damir Khabibullin³  Elizabeth P. Henske³  Doug A. Medvetz³  Tanja Schlechter⁴  Ilse Hofmann⁴  Elena A. Goncharova⁵  Vera P. Krymskaya⁵  Pat P. Ongusaha⁶  James K. Liao⁶ 

[1] Department of Biomedical Engineering, Columbia University, New York, New York, United States of America;Department of Dermatology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, United States of America;Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, United States of America;Joint Research Division Vascular Biology, Medical Faculty Mannheim and German Cancer Research Center (DKFZ-ZMBH-Alliance), Mannheim, Germany;Pulmonary, Allergy and Critical Care Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America;Vascular Medicine Research Unit, Brigham & Women’s Hospital and Harvard Medical School, Boston, Massachusetts, United States of America

关键词: Desmosomes;    Renal cell carcinoma;    Keratins;    Cell polarity;    Epidermis;    Pathogenesis;    Lung and intrathoracic tumors;    Secondary lung tumors;   

DOI  :  10.1371/journal.pone.0047842

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

Birt-Hogg-Dube (BHD) is a tumor suppressor gene syndrome associated with fibrofolliculomas, cystic lung disease, and chromophobe renal cell carcinoma. In seeking to elucidate the pathogenesis of BHD, we discovered a physical interaction between folliculin (FLCN), the protein product of the BHD gene, and p0071, an armadillo repeat containing protein that localizes to the cytoplasm and to adherens junctions. Adherens junctions are one of the three cell-cell junctions that are essential to the establishment and maintenance of the cellular architecture of all epithelial tissues. Surprisingly, we found that downregulation of FLCN leads to increased cell-cell adhesion in functional cell-based assays and disruption of cell polarity in a three-dimensional lumen-forming assay, both of which are phenocopied by downregulation of p0071. These data indicate that the FLCN-p0071 protein complex is a negative regulator of cell-cell adhesion. We also found that FLCN positively regulates RhoA activity and Rho-associated kinase activity, consistent with the only known function of p0071. Finally, to examine the role of Flcn loss on cell-cell adhesion in vivo, we utilized keratin-14 cre-recombinase (K14-cre) to inactivate Flcn in the mouse epidermis. The K14-Cre-Bhdflox/flox mice have striking delays in eyelid opening, wavy fur, hair loss, and epidermal hyperplasia with increased levels of mammalian target of rapamycin complex 1 (mTORC1) activity. These data support a model in which dysregulation of the FLCN-p0071 interaction leads to alterations in cell adhesion, cell polarity, and RhoA signaling, with broad implications for the role of cell-cell adhesion molecules in the pathogenesis of human disease, including emphysema and renal cell carcinoma.

【 授权许可】

CC BY