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The small GTPase Rab5c is a key regulator of trafficking of the CD93/Multimerin-2/1 integrin complex in endothelial cell adhesion and migration
Univ Siena, Dept Biotechnol Chem & Pharm, Via A Moro 2, I-53100 Siena, Italy.
Univ Siena, Dept Biotechnol Chem & Pharm, Via A Moro 2, I-53100 Siena, Italy.
Univ Siena, Dept Biotechnol Chem & Pharm, Via A Moro 2, I-53100 Siena, Italy.
Univ Siena, Dept Biotechnol Chem & Pharm, Via A Moro 2, I-53100 Siena, Italy.
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2019 (English)In: Cell Communication and Signaling, ISSN 1478-811X, E-ISSN 1478-811X, Vol. 17, article id 55Article in journal (Refereed) Published
Abstract [en]

Background

In the endothelium, the single-pass membrane protein CD93, through its interaction with the extracellular matrix protein Multimerin-2, activates signaling pathways that are critical for vascular development and angiogenesis. Trafficking of adhesion molecules through endosomal compartments modulates their signaling output. However, the mechanistic basis coordinating CD93 recycling and its implications for endothelial cell (EC) function remain elusive.

Methods

Human umbilical vein ECs (HUVECs) and human dermal blood ECs (HDBEC) were used in this study. Fluorescence confocal microscopy was employed to follow CD93 retrieval, recycling, and protein colocalization in spreading cells. To better define CD93 trafficking, drug treatments and transfected chimeric wild type and mutant CD93 proteins were used. The scratch assay was used to evaluate cell migration. Gene silencing strategies, flow citometry, and quantification of migratory capability were used to determine the role of Rab5c during CD93 recycling to the cell surface.

Results

Here, we identify the recycling pathway of CD93 following EC adhesion and migration. We show that the cytoplasmic domain of CD93, by its interaction with Moesin and F-actin, is instrumental for CD93 retrieval in adhering and migrating cells and that aberrant endosomal trafficking of CD93 prevents its localization at the leading edge of migration. Moreover, the small GTPase Rab5c turns out to be a key component of the molecular machinery that is able to drive CD93 recycling to the EC surface. Finally, in the Rab5c endosomal compartment CD93 forms a complex with Multimerin-2 and active 1 integrin, which is recycled back to the basolaterally-polarized cell surface by clathrin-independent endocytosis.

Conclusions

Our findings, focusing on the pro-angiogenic receptor CD93, unveil the mechanisms of its polarized trafficking during EC adhesion and migration, opening novel therapeutic opportunities for angiogenic diseases.

Place, publisher, year, edition, pages
2019. Vol. 17, article id 55
Keywords [en]
Cell polarity, Cell spreading, Moesin, C1qRp
National Category
Cell and Molecular Biology Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-387584DOI: 10.1186/s12964-019-0375-xISI: 000469353900001PubMedID: 31138217OAI: oai:DiVA.org:uu-387584DiVA, id: diva2:1331364
Available from: 2019-06-26 Created: 2019-06-26 Last updated: 2019-06-26Bibliographically approved

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