PMID- 25395669
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20141216
LR  - 20240214
IS  - 2046-6390 (Print)
IS  - 2046-6390 (Electronic)
IS  - 2046-6390 (Linking)
VI  - 3
IP  - 12
DP  - 2014 Nov 13
TI  - Genetic interaction implicates iRhom2 in the regulation of EGF receptor 
      signalling in mice.
PG  - 1151-7
LID - 10.1242/bio.201410116 [doi]
AB  - iRhoms are closely related to rhomboid intramembrane proteases but lack catalytic 
      activity. In mammals iRhoms are known to regulate the trafficking of TACE, the 
      protease that cleaves the membrane bound inflammatory cytokine TNF. We have 
      mapped a spontaneously occurring mouse mutation with a loss of hair phenotype, 
      curly bare (cub), to the Rhbdf2 locus, which encodes the iRhom2 protein. The cub 
      deletion removes the first 268 amino acids of the iRhom2 protein but is not a 
      loss of function. We have also identified a previously reported suppressor of 
      cub, called Mcub (modifier of curly bare), and find it to be a loss of function 
      allele of the amphiregulin gene (Areg). Amphiregulin is an activating ligand of 
      the epidermal growth factor receptor (EGFR) that, like TNF, is released by TACE. 
      Our results therefore imply a regulatory link between iRhoms and EGFR signalling 
      in mammals. We have tested the model that the cub mutation leads to iRhom2 
      hyperactivity and consequently excess TACE processing of amphiregulin and 
      elevated EGFR signalling. Our results do not support this hypothesis: we find 
      that, compared to wild-type cells, cub mutant embryonic fibroblasts release less 
      amphiregulin, and that the cub mutant form of iRhom2 is less able than wild type 
      to bind to TACE and promote its maturation.
CI  - (c) 2014. Published by The Company of Biologists Ltd.
FAU - Siggs, Owen M
AU  - Siggs OM
AD  - Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
FAU - Grieve, Adam
AU  - Grieve A
AD  - Dunn School of Pathology, South Parks Road, Oxford OX1 3RE, UK.
FAU - Xu, Hongmei
AU  - Xu H
AD  - Dunn School of Pathology, South Parks Road, Oxford OX1 3RE, UK.
FAU - Bambrough, Paul
AU  - Bambrough P
AD  - Dunn School of Pathology, South Parks Road, Oxford OX1 3RE, UK.
FAU - Christova, Yonka
AU  - Christova Y
AD  - Dunn School of Pathology, South Parks Road, Oxford OX1 3RE, UK.
FAU - Freeman, Matthew
AU  - Freeman M
AD  - Dunn School of Pathology, South Parks Road, Oxford OX1 3RE, UK 
      matthew.freeman@path.ox.ac.uk.
LA  - eng
GR  - 101035/WT_/Wellcome Trust/United Kingdom
GR  - 100083/WT_/Wellcome Trust/United Kingdom
GR  - MC_U105178780/MRC_/Medical Research Council/United Kingdom
GR  - G0900747/MRC_/Medical Research Council/United Kingdom
GR  - WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
DEP - 20141113
PL  - England
TA  - Biol Open
JT  - Biology open
JID - 101578018
PMC - PMC4265752
OTO - NOTNLM
OT  - ADAM17
OT  - Amphiregulin
OT  - Mouse
OT  - Rhbdf2
OT  - Rhomboid
OT  - TACE
OT  - iRhom
COIS- Competing interests: The authors have no competing interests to declare.
EDAT- 2014/11/15 06:00
MHDA- 2014/11/15 06:01
PMCR- 2014/11/13
CRDT- 2014/11/15 06:00
PHST- 2014/11/15 06:00 [entrez]
PHST- 2014/11/15 06:00 [pubmed]
PHST- 2014/11/15 06:01 [medline]
PHST- 2014/11/13 00:00 [pmc-release]
AID - bio.201410116 [pii]
AID - BIO201410116 [pii]
AID - 10.1242/bio.201410116 [doi]
PST - epublish
SO  - Biol Open. 2014 Nov 13;3(12):1151-7. doi: 10.1242/bio.201410116.