The RGD integrin binding site in human L1-CAM is important for nuclear signaling
Copyright policy )The RGD integrin binding site in human L1-CAM is important for nuclear signaling
L1 cell adhesion molecule (L1-CAM) is a transmembrane cell adhesion molecule initially defined as a promigratory molecule in the developing nervous system. L1 is also overexpressed in a variety of human carcinomas and is associated with bad prognosis. In carcinoma cell lines L1 augments cell motility and metastasis, tumor growth in nude mice and induces expression of L1-dependent genes. It is not known whether L1-signaling requires ligand binding. The RGD motif in the sixth Ig domain of L1 is a binding site for integrins. In the present study we analyzed the role of RGDs in L1-signaling using site-directed mutagenesis combined with antibody blocking studies. We observed that L1-RGE expressing HEK293 cells showed reduced cell-cell binding, cell motility, invasiveness and tumor growth in NOD/SCID mice. The RGE-mutation impaired L1-dependent gene regulation and antibodies to alphavbeta5 integrin had similar effects. Mutant L1 was unable to translocate to the nucleus. Our findings highlight the importance of the RGD site in L1 for human tumors and suggest that nuclear signaling of L1 is dependent on integrins.
- French Institute of Health and Medical Research France
- Kiel University Germany
- German Cancer Research Center Germany
Cell Nucleus, Integrins, Binding Sites, Active Transport, Cell Nucleus, Neural Cell Adhesion Molecule L1, CHO Cells, Cell Communication, Mice, SCID, Mice, Cricetulus, Gene Expression Regulation, Cell Movement, Mice, Inbred NOD, Cricetinae, Cell Adhesion, Animals, Humans, Female, Cells, Cultured, Gene Deletion
Cell Nucleus, Integrins, Binding Sites, Active Transport, Cell Nucleus, Neural Cell Adhesion Molecule L1, CHO Cells, Cell Communication, Mice, SCID, Mice, Cricetulus, Gene Expression Regulation, Cell Movement, Mice, Inbred NOD, Cricetinae, Cell Adhesion, Animals, Humans, Female, Cells, Cultured, Gene Deletion
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