Authors
Nicholas Johnson, Jan Dohnálek, Jana Březinová, Josef Čáslavský, Aneta Škarková, Njainday Jobe, Monika Fliegl, Květa Trávníčková, Emma Burbridge, Vahap Canbay, Chatpakorn Rassameena Christiansen, Ulrich Auf dem Keller, Juraj Lábaj, Olha Fedosieieva, Jan Procházka, Daniel Rösel, Jan Brábek, Tomáš Vomastek, Colin Adrain, Kvido Stříšovský
Published in
Cellular and molecular life sciences : CMLS. Volume 83. Issue 1. Aug 17, 2026. Epub Aug 17, 2026.
Abstract
Signalling via the epidermal growth factor receptor (EGFR) is indispensable for morphogenesis and tissue homeostasis. It is activated by extracellular ligands, typically released from transmembrane precursors by proteolysis. Ligand shedding activity is provided by the conserved rhomboid intramembrane serine proteases in Drosophila, but by the unrelated ADAM family metalloproteases in mammals, leaving the functions of mammalian non-mitochondrial rhomboids underexplored. Using quantitative proteomics, we show that EGFR is the main endogenous substrate of the human rhomboid protease RHBDL2 in keratinocytes. By shedding the EGFR ectodomain, thus producing a decoy receptor, RHBDL2 suppresses EGFR signalling, limiting cell migration and invasion. Conspicuously, RHBDL2 activity is upregulated by elevated intracellular calcium concentration, a condition typical of keratinocyte differentiation. These effects are recapitulated in primary human keratinocytes, and human skin equivalents deficient in RHBDL2 display incomplete differentiation and are morphologically disordered compared to wild-type cells. We propose that context-specific fine-tuning of EGFR signalling and sensitivity to cross-talk from other signalling pathways could be important and hitherto overlooked roles of rhomboid proteases in mammals.
PMID:
42771030
Bibliographic data and abstract were imported from PubMed on 22 Sep 2026.
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