@article{4d59c0c2d3994ad4b3fa82ed3bcd1078,
title = "Adherens junctions organize size-selective proteolytic hotspots critical for Notch signalling",
abstract = "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.",
author = "Minsuk Kwak and Southard, {Kaden M.} and Kim, {Woon Ryoung} and Annie Lin and Kim, {Nam Hyeong} and Ramu Gopalappa and Lee, {Hyun Jung} and Minji An and Choi, {Seo Hyun} and Yunmin Jung and Kunwoo Noh and Justin Farlow and Anastasios Georgakopoulos and Robakis, {Nikolaos K.} and Kang, {Min K.} and Kutys, {Matthew L.} and Daeha Seo and Kim, {Hyongbum Henry} and Kim, {Yong Ho} and Jinwoo Cheon and Gartner, {Zev J.} and Jun, {Young wook}",
note = "Funding Information: The authors thank S. Blacklow (Harvard U.), C. Miller (King{\textquoteright}s College London) and K. Shimamura (Kumamoto U.) for the kind gifts of Notch, APP and DN-cadherin plasmids, respectively. We also thank A. Balmain, M. Moasser and E. Collison (UCSF) for sharing cell lines. D. Fletcher (UC Berkeley), A. Joffe (UC Berkeley) and D. Al-Rawi (Stanford U.) provided insightful discussion. For reagents, technical support, and discussions, we thank the Kim, Cheon, Gartner and Jun laboratories, as well as the Nikon Imaging Center and Wynton at UCSF. M.K. was supported by a Life Science Research Foundation fellowship as the Shurl and Kay Curci Foundation fellow, and by Burroughs Wellcome Travel Fund. This work was supported by NRF, NRF-2021R1F1A1063378 (M.K.), NRF-2018R1A5A1025511 (D.S.) and NRF-2017R1A2B3004198 (H.H.K.), HI17C0676 from Korean Ministry of Health and Welfare (H.H.K.), 5R01NS047229 from National Institute on Aging (NIA) and the National Institute of Health (NIH) (A.G.), 5R01AG008200 from National Institute on Aging (NIA) and the National Institute of Health (NIH) (N.K.R.), IBS-R026-D1 from IBS (M.K., H.H.K. and J.C.), NRF-2019R1A2C1085712 (Y.H.K.), the UCSF Center for Cellular Construction (an NSF Science and Technology Center, no. DBI-1548297) (Z.J.G.), U01CA244109 from the National Cancer Institute (Z.J.G.), 1R01GM112081, 1R01GM126542-01 and R35GM134948 from the National Institute of General Medical Science (NIGMS) and the NIH (Y.Jun), 1R21AG072232-01 from the National Institute on Aging (NIA) and the NIH (M.L.K. and Y.Jun), R00CA226366 from the National Cancer Institute (M.L.K) and NIH, and the UCSF Program for Breakthrough Biomedical Research (PBBR) funded in part by the Sandler Foundation (M.L.K and Y.Jun). Z.J.G. is a Chan Zuckerberg BioHub Investigator. Funding Information: The authors thank S. Blacklow (Harvard U.), C. Miller (King{\textquoteright}s College London) and K. Shimamura (Kumamoto U.) for the kind gifts of Notch, APP and DN-cadherin plasmids, respectively. We also thank A. Balmain, M. Moasser and E. Collison (UCSF) for sharing cell lines. D. Fletcher (UC Berkeley), A. Joffe (UC Berkeley) and D. Al-Rawi (Stanford U.) provided insightful discussion. For reagents, technical support, and discussions, we thank the Kim, Cheon, Gartner and Jun laboratories, as well as the Nikon Imaging Center and Wynton at UCSF. M.K. was supported by a Life Science Research Foundation fellowship as the Shurl and Kay Curci Foundation fellow, and by Burroughs Wellcome Travel Fund. This work was supported by NRF, NRF-2021R1F1A1063378 (M.K.), NRF-2018R1A5A1025511 (D.S.) and NRF-2017R1A2B3004198 (H.H.K.), HI17C0676 from Korean Ministry of Health and Welfare (H.H.K.), 5R01NS047229 from National Institute on Aging (NIA) and the National Institute of Health (NIH) (A.G.), 5R01AG008200 from National Institute on Aging (NIA) and the National Institute of Health (NIH) (N.K.R.), IBS-R026-D1 from IBS (M.K., H.H.K. and J.C.), NRF-2019R1A2C1085712 (Y.H.K.), the UCSF Center for Cellular Construction (an NSF Science and Technology Center, no. DBI-1548297) (Z.J.G.), U01CA244109 from the National Cancer Institute (Z.J.G.), 1R01GM112081, 1R01GM126542-01 and R35GM134948 from the National Institute of General Medical Science (NIGMS) and the NIH (Y.Jun), 1R21AG072232-01 from the National Institute on Aging (NIA) and the NIH (M.L.K. and Y.Jun), R00CA226366 from the National Cancer Institute (M.L.K) and NIH, and the UCSF Program for Breakthrough Biomedical Research (PBBR) funded in part by the Sandler Foundation (M.L.K and Y.Jun). Z.J.G. is a Chan Zuckerberg BioHub Investigator. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2022",
month = dec,
doi = "10.1038/s41556-022-01031-6",
language = "English",
volume = "24",
pages = "1739--1753",
journal = "Nature Cell Biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "12",
}