Adherens junctions organize size-selective proteolytic hotspots critical for Notch signalling

Minsuk Kwak, Kaden M. Southard, Woon Ryoung Kim, Annie Lin, Nam Hyeong Kim, Ramu Gopalappa, Hyun Jung Lee, Minji An, Seo Hyun Choi, Yunmin Jung, Kunwoo Noh, Justin Farlow, Anastasios Georgakopoulos, Nikolaos K. Robakis, Min K. Kang, Matthew L. Kutys, Daeha Seo, Hyongbum Henry Kim, Yong Ho Kim, Jinwoo CheonZev J. Gartner, Young wook Jun

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


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 γ-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 γ-secretase and primed receptors while excluding full-length Notch. AJs induce these functionally distinct microdomains by means of lipid-dependent γ-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 γ-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 γ-secretase processing of multiple transmembrane proteins regulating development, homeostasis and disease.

Original languageEnglish
Pages (from-to)1739-1753
Number of pages15
JournalNature Cell Biology
Issue number12
StatePublished - Dec 2022


Dive into the research topics of 'Adherens junctions organize size-selective proteolytic hotspots critical for Notch signalling'. Together they form a unique fingerprint.

Cite this