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Genome-wide screen of gamma-secretase–mediated intramembrane cleavage of receptor tyrosine kinases
Receptor tyrosine kinases (RTKs) have been demonstrated to signal via regulated intramembrane proteolysis, in which ectodomain shedding and subsequent intramembrane cleavage by gamma-secretase leads to release of a soluble intracellular receptor fragment with functional activity. For most RTKs, howe...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662267/ https://www.ncbi.nlm.nih.gov/pubmed/28904208 http://dx.doi.org/10.1091/mbc.E17-04-0261 |
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author | Merilahti, Johannes A. M. Ojala, Veera K. Knittle, Anna M. Pulliainen, Arto T. Elenius, Klaus |
author_facet | Merilahti, Johannes A. M. Ojala, Veera K. Knittle, Anna M. Pulliainen, Arto T. Elenius, Klaus |
author_sort | Merilahti, Johannes A. M. |
collection | PubMed |
description | Receptor tyrosine kinases (RTKs) have been demonstrated to signal via regulated intramembrane proteolysis, in which ectodomain shedding and subsequent intramembrane cleavage by gamma-secretase leads to release of a soluble intracellular receptor fragment with functional activity. For most RTKs, however, it is unknown whether they can exploit this new signaling mechanism. Here we used a system-wide screen to address the frequency of susceptibility to gamma-secretase cleavage among human RTKs. The screen covering 45 of the 55 human RTKs identified 12 new as well as all nine previously published gamma-secretase substrates. We biochemically validated the screen by demonstrating that the release of a soluble intracellular fragment from endogenous AXL was dependent on the sheddase disintegrin and metalloprotease 10 (ADAM10) and the gamma-secretase component presenilin-1. Functional analysis of the cleavable RTKs indicated that proliferation promoted by overexpression of the TAM family members AXL or TYRO3 depends on gamma-secretase cleavage. Taken together, these data indicate that gamma-secretase–mediated cleavage provides an additional signaling mechanism for numerous human RTKs. |
format | Online Article Text |
id | pubmed-5662267 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-56622672018-01-16 Genome-wide screen of gamma-secretase–mediated intramembrane cleavage of receptor tyrosine kinases Merilahti, Johannes A. M. Ojala, Veera K. Knittle, Anna M. Pulliainen, Arto T. Elenius, Klaus Mol Biol Cell Articles Receptor tyrosine kinases (RTKs) have been demonstrated to signal via regulated intramembrane proteolysis, in which ectodomain shedding and subsequent intramembrane cleavage by gamma-secretase leads to release of a soluble intracellular receptor fragment with functional activity. For most RTKs, however, it is unknown whether they can exploit this new signaling mechanism. Here we used a system-wide screen to address the frequency of susceptibility to gamma-secretase cleavage among human RTKs. The screen covering 45 of the 55 human RTKs identified 12 new as well as all nine previously published gamma-secretase substrates. We biochemically validated the screen by demonstrating that the release of a soluble intracellular fragment from endogenous AXL was dependent on the sheddase disintegrin and metalloprotease 10 (ADAM10) and the gamma-secretase component presenilin-1. Functional analysis of the cleavable RTKs indicated that proliferation promoted by overexpression of the TAM family members AXL or TYRO3 depends on gamma-secretase cleavage. Taken together, these data indicate that gamma-secretase–mediated cleavage provides an additional signaling mechanism for numerous human RTKs. The American Society for Cell Biology 2017-11-01 /pmc/articles/PMC5662267/ /pubmed/28904208 http://dx.doi.org/10.1091/mbc.E17-04-0261 Text en © 2017 Merilahti et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. |
spellingShingle | Articles Merilahti, Johannes A. M. Ojala, Veera K. Knittle, Anna M. Pulliainen, Arto T. Elenius, Klaus Genome-wide screen of gamma-secretase–mediated intramembrane cleavage of receptor tyrosine kinases |
title | Genome-wide screen of gamma-secretase–mediated intramembrane cleavage of receptor tyrosine kinases |
title_full | Genome-wide screen of gamma-secretase–mediated intramembrane cleavage of receptor tyrosine kinases |
title_fullStr | Genome-wide screen of gamma-secretase–mediated intramembrane cleavage of receptor tyrosine kinases |
title_full_unstemmed | Genome-wide screen of gamma-secretase–mediated intramembrane cleavage of receptor tyrosine kinases |
title_short | Genome-wide screen of gamma-secretase–mediated intramembrane cleavage of receptor tyrosine kinases |
title_sort | genome-wide screen of gamma-secretase–mediated intramembrane cleavage of receptor tyrosine kinases |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662267/ https://www.ncbi.nlm.nih.gov/pubmed/28904208 http://dx.doi.org/10.1091/mbc.E17-04-0261 |
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