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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...

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Autores principales: Merilahti, Johannes A. M., Ojala, Veera K., Knittle, Anna M., Pulliainen, Arto T., Elenius, Klaus
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2017
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.
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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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