A1 Refereed original research article in a scientific journal

Genome-wide screen of gamma-secretase-mediated intramembrane cleavage of receptor tyrosine kinases




AuthorsMerilahti JAM, Ojala VK, Knittle AM, Pulliainen AT, Elenius K

PublisherAMER SOC CELL BIOLOGY

Publication year2017

JournalMolecular Biology of the Cell

Journal name in sourceMOLECULAR BIOLOGY OF THE CELL

Journal acronymMOL BIOL CELL

Volume28

Issue22

First page 3123

Last page3131

Number of pages9

ISSN1059-1524

eISSN1939-4586

DOIhttps://doi.org/10.1091/mbc.E17-04-0261(external)

Self-archived copy’s web addresshttps://research.utu.fi/converis/portal/detail/Publication/27880496(external)


Abstract
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.

Downloadable publication

This is an electronic reprint of the original article.
This reprint may differ from the original in pagination and typographic detail. Please cite the original version.





Last updated on 2024-26-11 at 22:14