Memo has a novel role in S1P signaling and crucial for vascular development

Kondo, Shunya; Bottos, Alessia; Allegood, Jeremy C.; Masson, Regis; Maurer, Francisca G.; Genoud, Christel; Kaeser, Patrick; Huwiler, Andrea; Murakami, Masato; Spiegel, Sarah; Hynes, Nancy E. (2014). Memo has a novel role in S1P signaling and crucial for vascular development. PLoS ONE, 9(4), e94114. Public Library of Science 10.1371/journal.pone.0094114

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Memo is a conserved protein that was identified as an essential mediator of tumor cell motility induced by receptor tyrosine kinase activation. Here we show that Memo null mouse embryonic fibroblasts (MEFs) are impaired in PDGF-induced migration and this is due to a defect in sphingosine-1-phosphate (S1P) signaling. S1P is a bioactive phospholipid produced in response to multiple stimuli, which regulates many cellular processes. S1P is secreted to the extracellular milieu where it exerts its function by binding a family of G-protein coupled receptors (S1PRs), causing their activation in an autocrine or paracrine manner. The process, termed cell-autonomous S1PR signaling, plays a role in survival and migration. Indeed, PDGF uses cell-autonomous S1PR signaling to promote cell migration; we show here that this S1P pathway requires Memo. Using vascular endothelial cells (HUVECs) with Memo knock-down we show that their survival in conditions of serum-starvation is impaired. Furthermore, Memo loss in HUVECs causes a reduction of junctional VE-cadherin and an increase in sprout formation. Each of these phenotypes is rescued by S1P or S1P agonist addition, showing that Memo also plays an important role in cell-autonomous S1PR signaling in endothelial cells. We also produced conventional and endothelial cell-specific conditional Memo knock-out mouse strains and show that Memo is essential for embryonic development. Starting at E13.5 embryos of both strains display bleeding and other vascular problems, some of the phenotypes that have been described in mouse strains lacking S1PRs. The essential role of Memo in embryonic vascular development may be due in part to alterations in S1P signaling. Taken together our results show that Memo has a novel role in the S1P pathway and that Memo is needed to promote cell-autonomous S1PR activation.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology

UniBE Contributor:

Huwiler, Andrea

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1932-6203

Publisher:

Public Library of Science

Language:

English

Submitter:

Anita Dähler

Date Deposited:

19 Jan 2015 14:44

Last Modified:

20 Jan 2015 19:27

Publisher DOI:

10.1371/journal.pone.0094114

PubMed ID:

24714781

BORIS DOI:

10.7892/boris.62035

URI:

https://boris.unibe.ch/id/eprint/62035

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