Trans- dimerization of JAM-A regulates Rap2 and is mediated by a domain that is distinct from the cis- dimerization interface
Year: 2014
Type: article
Abstract: Junctional adhesion molecule-A (JAM-A) is a tight junction-associated signaling protein that regulates epithelial cell proliferation, migration, and barrier function. JAM-A dimerization on a common cell surface (in cis) has been shown to regulate cell migration, and evidence suggests that JAM-A may form homodimers between cells (in trans). Indeed, transfection experiments revealed accumulation of JAM-A at sites between transfected cells, which was lost in cells expressing cis- or predicted trans-dimerization null mutants. Of importance, microspheres coated with JAM-A containing alanine substitutions to residues 43NNP45 (NNP-JAM-A) within the predicted trans-dimerization site did not aggregate. In contrast, beads coated with cis-null JAM-A demonstrated enhanced clustering similar to that observed with wild-type (WT) JAM-A. In addition, atomic force microscopy revealed decreased association forces in NNP-JAM-A compared with WT and cis-null JAM-A. Assessment of effects of JAM-A dimerization on cell signaling revealed that expression of trans- but not cis-null JAM-A mutants decreased Rap2 activity. Furthermore, confluent cells, which enable trans-dimerization, had enhanced Rap2 activity. Taken together, these results suggest that trans-dimerization of JAM-A occurs at a unique site and with different affinity compared with dimerization in cis. Trans-dimerization of JAM-A may thus act as a barrier-inducing molecular switch that is activated when cells become confluent.
Source: Molecular Biology of the Cell
Language: English
Subfield: Immunology and Allergy
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Vanderbilt University, Vanderbilt-Ingram Cancer Center, Deutsche Forschungsgemeinschaft, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke
Awards: Molecular Basis of Reovirus Pathogenesis, Intestinal mucosal wound resealing, Emory Epithelial Pathobiology Research Development Center, Blood Brain Barrier Penetration by Neurotropic Reovirus, G2304076072, Molecular Basis of Reovirus Pathogenesis, G2378209405, G275963511, Structure function studies in intestinal epithelial JAM, Structural Analysis of Reovirus Attachment Mechanisms, G310177190, G344109072, Medical Scientist Training Program, G3865556588, G3989539122, Neutrophil Interactions with Intestinal Epithelial Cells, G5853943267, INTESTINAL MUCOSAL WOUND RESEALING IN SURGICAL DISEASES, Regulation of intestinal epithelial barrier function by intercellular junction proteins in health and disease, Diabetes Research and Training Center, G9000100511, G9000106052, G9000153420, G9000168360, Molecular and Cellular Basis for Digestive Diseases, Cancer Center Support Grant, Intestinal Inflammation: Signaling proteins and the rate of PMN transmigration, Vanderbilt Diabetes Research Center
OpenAlex ID: W2165332894