| Title: |
Angiogenesis is limited by LIC1-mediated lysosomal trafficking. |
| Authors: |
Johnson, Dymonn, Colijn, Sarah, Richee, Jahmiera, Yano, Joseph, Burns, Margaret, Davis, Andrew E., Pham, Van N., Saric, Amra, Jain, Akansha, Yin, Ying, Castranova, Daniel, Melani, Mariana, Fujita, Misato, Grainger, Stephanie, Bonifacino, Juan S., Weinstein, Brant M., Stratman, Amber N. |
| Source: |
Angiogenesis; Nov2024, Vol. 27 Issue 4, p943-962, 20p |
| Subject Terms: |
ADAPTOR proteins, DYNEIN, ENDOTHELIAL cells, NEOVASCULARIZATION, ENDOSOMES |
| 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. [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |
