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CEP 41‐mediated ciliary tubulin glutamylation drives angiogenesis through AURKA ‐dependent deciliation
Author(s) -
Ki Soo Mi,
Kim Ji Hyun,
Won So Yeon,
Oh Shin Ji,
Lee In Young,
Bae YoungKi,
Chung Ki Wha,
Choi ByungOk,
Park Boyoun,
Choi EuiJu,
Lee Ji Eun
Publication year - 2019
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201948290
Subject(s) - angiogenesis , microbiology and biotechnology , chemistry , biology , cancer research
The endothelial cilium is a microtubule‐based organelle responsible for blood flow‐induced mechanosensation and signal transduction during angiogenesis. The precise function and mechanisms by which ciliary mechanosensation occurs, however, are poorly understood. Although posttranslational modifications ( PTM s) of cytoplasmic tubulin are known to be important in angiogenesis, the specific roles of ciliary tubulin PTM s play remain unclear. Here, we report that loss of centrosomal protein 41 ( CEP 41) results in vascular impairment in human cell lines and zebrafish, implying a previously unknown pro‐angiogenic role for CEP 41. We show that proper control of tubulin glutamylation by CEP 41 is necessary for cilia disassembly and that is involved in endothelial cell ( EC ) dynamics such as migration and tubulogenesis. We show that in EC s responding to shear stress or hypoxia, CEP 41 activates Aurora kinase A ( AURKA ) and upregulates expression of VEGFA and VEGFR 2 through ciliary tubulin glutamylation , as well as leads to the deciliation. We further show that in hypoxia‐induced angiogenesis, CEP 41 is responsible for the activation of HIF 1α to trigger the AURKA ‐ VEGF pathway. Overall, our results suggest the CEP 41‐ HIF 1α‐ AURKA ‐ VEGF axis as a key molecular mechanism of angiogenesis and demonstrate how important ciliary tubulin glutamylation is in mechanosense‐responded EC dynamics.