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Plasma membrane-derived extracellular microvesicles mediate non-canonical intercellular NOTCH signaling
1Program in Molecular and Integrative Physiological Sciences, Department of Environment Health, Harvard T.H. Chan School of Public Health, 665 Huntington Ave., Boston, MA, 02115, USA.
Nature Communications
|September 29, 2017
Summary
Arrestin domain-containing protein 1-mediated microvesicles (ARMMs) transfer active NOTCH receptors between cells. This novel pathway mediates intercellular NOTCH signaling independently of direct cell contact.
Area of Science:
- Cell Biology
- Molecular Biology
- Extracellular Vesicles
Background:
- Arrestin domain-containing protein 1-mediated microvesicles (ARMMs) are extracellular vesicles originating from the plasma membrane.
- The molecular composition and physiological roles of ARMMs remain largely uncharacterized.
Purpose of the Study:
- To investigate the molecular composition of ARMMs.
- To determine the role of ARMMs in intercellular signaling, specifically focusing on NOTCH signaling.
Main Methods:
- Proteomic analysis of purified ARMMs to identify enriched proteins.
- Investigating the presence and function of NOTCH receptors within ARMMs.
- Assessing the transfer of ARMMs and their cargo to recipient cells.
Main Results:
- Over 100 proteins, including ARRDC1, TSG101, ESCRT components, and plasma membrane proteins like NOTCH2, are enriched in ARMMs.
- NOTCH2 incorporation into ARMMs is mediated by the ITCH E3 ligase and ADAM10 metalloprotease.
- ARMMs deliver functional NOTCH2 to recipient cells, inducing NOTCH-specific gene expression upon γ-secretase cleavage.
Conclusions:
- ARMMs facilitate a novel, non-canonical intercellular NOTCH signaling pathway.
- This pathway operates over a distance and is independent of direct cell-cell contact, mediated by the transfer of active NOTCH receptors via ARMMs.
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