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Proc Natl Acad Sci U S A. 2017 Nov 21;114(47):12495-12500. doi: 10.1073/pnas.1713433114. Epub 2017 Nov 6.

Syntenin mediates SRC function in exosomal cell-to-cell communication.

Imjeti NS1,2,3,4, Menck K2,3,4, Egea-Jimenez AL1,2,3,4, Lecointre C5, Lembo F2,3,4, Bouguenina H2,3,4, Badache A2,3,4, Ghossoub R2,3,4, David G1,2,3,4, Roche S5, Zimmermann P6,2,3,4.

Author information

1
Department of Human Genetics, K. U. Leuven, B-3000 Leuven, Belgium.
2
Centre de Recherche en Cancérologie de Marseille (CRCM), Aix-Marseille Université, Marseille F-13284, France.
3
Inserm, U1068, Institut Paoli-Calmettes, Marseille F-13009, France.
4
CNRS, UMR7258, Marseille F-13009, France.
5
CNRS Université Montpellier, Centre de Recherche en Biologie Cellulaire de Montpellier, 34000 Montpellier, France.
6
Department of Human Genetics, K. U. Leuven, B-3000 Leuven, Belgium; pascale.zimmermann@kuleuven.be.

Abstract

The cytoplasmic tyrosine kinase SRC controls cell growth, proliferation, adhesion, and motility. The current view is that SRC acts primarily downstream of cell-surface receptors to control intracellular signaling cascades. Here we reveal that SRC functions in cell-to-cell communication by controlling the biogenesis and the activity of exosomes. Exosomes are viral-like particles from endosomal origin that can reprogram recipient cells. By gain- and loss-of-function studies, we establish that SRC stimulates the secretion of exosomes having promigratory activity on endothelial cells and that syntenin is mandatory for SRC exosomal function. Mechanistically, SRC impacts on syndecan endocytosis and on syntenin-syndecan endosomal budding, upstream of ARF6 small GTPase and its effector phospholipase D2, directly phosphorylating the conserved juxtamembrane DEGSY motif of the syndecan cytosolic domain and syntenin tyrosine 46. Our study uncovers a function of SRC in cell-cell communication, supported by syntenin exosomes, which is likely to contribute to tumor-host interactions.

KEYWORDS:

ARF6; SRC; exosome; syndecan; syntenin

PMID:
29109268
PMCID:
PMC5703317
DOI:
10.1073/pnas.1713433114
[Indexed for MEDLINE]
Free PMC Article

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