PUBLICATION
Angiogenesis is limited by LIC1-mediated lysosomal trafficking
- Authors
- Johnson, D., Colijn, S., Richee, J., Yano, J., Burns, M., Davis, A.E., Pham, V.N., Saric, A., Jain, A., Yin, Y., Castranova, D., Melani, M., Fujita, M., Grainger, S., Bonifacino, J.S., Weinstein, B.M., Stratman, A.N.
- ID
- ZDB-PUB-241003-2
- Date
- 2024
- Source
- Angiogenesis 27(4): 943-962 (Journal)
- Registered Authors
- Castranova, Dan, Colijn, Sarah, Davis, Andrew, Fujita, Misato, Johnson, Dymonn, Melani, Mariana, Pham, Van, Richee, Jahmiera, Stratman, Amber, Weinstein, Brant M., Yin, Ying
- Keywords
- Angiogenesis, Dynein motor, Endosomes, Lic1, Lysosomes, Rilp1/2, Zebrafish
- MeSH Terms
-
- Zebrafish*/genetics
- Zebrafish*/metabolism
- Humans
- Endosomes/metabolism
- Neovascularization, Physiologic*
- Cytoplasmic Dyneins/genetics
- Cytoplasmic Dyneins/metabolism
- Lysosomes*/metabolism
- Protein Transport*
- Animals
- src-Family Kinases/metabolism
- rab GTP-Binding Proteins*/genetics
- rab GTP-Binding Proteins*/metabolism
- Vascular Endothelial Growth Factor Receptor-2/genetics
- Vascular Endothelial Growth Factor Receptor-2/metabolism
- Angiogenesis
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- Mutation
- Human Umbilical Vein Endothelial Cells/metabolism
- Adaptor Proteins, Signal Transducing/genetics
- Adaptor Proteins, Signal Transducing/metabolism
- PubMed
- 39356418 Full text @ Angiogenesis
Citation
Johnson, D., Colijn, S., Richee, J., Yano, J., Burns, M., Davis, A.E., Pham, V.N., Saric, A., Jain, A., Yin, Y., Castranova, D., Melani, M., Fujita, M., Grainger, S., Bonifacino, J.S., Weinstein, B.M., Stratman, A.N. (2024) Angiogenesis is limited by LIC1-mediated lysosomal trafficking. Angiogenesis. 27(4):943-962.
Abstract
Dynein cytoplasmic 1 light intermediate chain 1 (LIC1, DYNC1LI1) is a core subunit of the dynein motor complex. The LIC1 subunit also interacts with various cargo adaptors to regulate Rab-mediated endosomal recycling and lysosomal degradation. Defects in this gene are predicted to alter dynein motor function, Rab binding capabilities, and cytoplasmic cargo trafficking. Here, we have identified a dync1li1 zebrafish mutant, harboring a premature stop codon at the exon 12/13 splice acceptor site, that displays increased angiogenesis. In vitro, LIC1-deficient human endothelial cells display increases in cell surface levels of the pro-angiogenic receptor VEGFR2, SRC phosphorylation, and Rab11-mediated endosomal recycling. In vivo, endothelial-specific expression of constitutively active Rab11a leads to excessive angiogenesis, similar to the dync1li1 mutants. Increased angiogenesis is also evident in zebrafish harboring mutations in rilpl1/2, the adaptor proteins that promote Rab docking to Lic1 to mediate lysosomal targeting. These findings suggest that LIC1 and the Rab-adaptor proteins RILPL1 and 2 restrict angiogenesis by promoting degradation of VEGFR2-containing recycling endosomes. Disruption of LIC1- and RILPL1/2-mediated lysosomal targeting increases Rab11-mediated recycling endosome activity, promoting excessive SRC signaling and angiogenesis.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping