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
- Lysosomes*/metabolism
- Cytoplasmic Dyneins/genetics
- Cytoplasmic Dyneins/metabolism
- PubMed
- 39356418 Full text @ Angiogenesis
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