A novel L1CAM isoform with angiogenic activity generated by NOVA2-mediated alternative splicing.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 30829570.
- Also identified by DOI 10.7554/eLife.44305 and PMC identifier 6398979.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
The biological players involved in angiogenesis are only partially defined. Here, we report that endothelial cells (ECs) express a novel isoform of the cell-surface adhesion molecule L1CAM, termed L1-ΔTM. The splicing factor NOVA2, which binds directly to <i>L1CAM</i> pre-mRNA, is necessary and sufficient for the skipping of L1CAM transmembrane domain in ECs, leading to the release of soluble L1-ΔTM. The latter exerts high angiogenic function through both autocrine and paracrine activities. Mechanistically, L1-ΔTM-induced angiogenesis requires fibroblast growth factor receptor-1 signaling, implying a crosstalk between the two molecules. NOVA2 and L1-ΔTM are overexpressed in the vasculature of ovarian cancer, where L1-ΔTM levels correlate with tumor vascularization, supporting the involvement of NOVA2-mediated L1-ΔTM production in tumor angiogenesis. Finally, high NOVA2 expression is associated with poor outcome in ovarian cancer patients. Our results point to L1-ΔTM as a novel, EC-derived angiogenic factor which may represent a target for innovative antiangiogenic therapies.
Medical subject headings
- Alternative Splicing
- Angiogenic Proteins
- Endothelial Cells
- Nerve Tissue Proteins
- Neural Cell Adhesion Molecule L1
- Protein Isoforms
- RNA-Binding Proteins