Other
22 Authors
- Robakis NK,
- Southard KM,
- Lin A,
- Kim YH,
- Kutys ML,
- Seo D,
- Farlow J,
- Jung Y,
- Noh K,
- Kim HH,
- Cheon J,
- Choi SH,
- Gopalappa R,
- Kang MK,
- Kim WR,
- An M,
- Lee HJ,
- Gartner ZJ,
- Georgakopoulos A,
- Jun YW,
- Kwak M,
- Kim NH
| First Author | Kwak M | Year | 2022 |
| Journal | Nat Cell Biol | Volume | 24 |
| Issue | 12 | Pages | 1739-1753 |
| PubMed ID | 36456828 | Mgi Jnum | J:332318 |
| Mgi Id | MGI:7414458 | Doi | 10.1038/s41556-022-01031-6 |
| Citation | Kwak M, et al. (2022) Adherens junctions organize size-selective proteolytic hotspots critical for Notch signalling. Nat Cell Biol 24(12):1739-1753 |
| abstractText | Adherens junctions (AJs) create spatially, chemically and mechanically discrete microdomains at cellular interfaces. Here, using a mechanogenetic platform that generates artificial AJs with controlled protein localization, clustering and mechanical loading, we find that AJs also organize proteolytic hotspots for gamma-secretase with a spatially regulated substrate selectivity that is critical in the processing of Notch and other transmembrane proteins. Membrane microdomains outside of AJs exclusively organize Notch ligand-receptor engagement (LRE microdomains) to initiate receptor activation. Conversely, membrane microdomains within AJs exclusively serve to coordinate regulated intramembrane proteolysis (RIP microdomains). They do so by concentrating gamma-secretase and primed receptors while excluding full-length Notch. AJs induce these functionally distinct microdomains by means of lipid-dependent gamma-secretase recruitment and size-dependent protein segregation. By excluding full-length Notch from RIP microdomains, AJs prevent inappropriate enzyme-substrate interactions and suppress spurious Notch activation. Ligand-induced ectodomain shedding eliminates size-dependent segregation, releasing Notch to translocate into AJs for processing by gamma-secretase. This mechanism directs radial differentiation of ventricular zone-neural progenitor cells in vivo and more broadly regulates the proteolysis of other large cell-surface receptors such as amyloid precursor protein. These findings suggest an unprecedented role of AJs in creating size-selective spatial switches that choreograph gamma-secretase processing of multiple transmembrane proteins regulating development, homeostasis and disease. |
