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The integrated stress response regulates BMP signalling through effects on translation.


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Authors

Malzer, Elke 
Dominicus, Caia S 
Chambers, Joseph E 
Dickens, Jennifer A 
Mookerjee, Souradip  ORCID logo  https://orcid.org/0000-0003-4904-1324

Abstract

BACKGROUND: Developmental pathways must be responsive to the environment. Phosphorylation of eIF2α enables a family of stress-sensing kinases to trigger the integrated stress response (ISR), which has pro-survival and developmental consequences. Bone morphogenetic proteins (BMPs) regulate multiple developmental processes in organisms from insects to mammals. RESULTS: Here we show in Drosophila that GCN2 antagonises BMP signalling through direct effects on translation and indirectly via the transcription factor crc (dATF4). Expression of a constitutively active GCN2 or loss of the eIF2α phosphatase dPPP1R15 impairs developmental BMP signalling in flies. In cells, inhibition of translation by GCN2 blocks downstream BMP signalling. Moreover, loss of d4E-BP, a target of crc, augments BMP signalling in vitro and rescues tissue development in vivo. CONCLUSION: These results identify a novel mechanism by which the ISR modulates BMP signalling during development.

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Keywords

4E-BP, ATF4, BMP, GCN2, PPP1R15, Translation, Animals, Bone Morphogenetic Proteins, Drosophila, Drosophila Proteins, Eukaryotic Initiation Factor-2, Gene Expression Regulation, Phosphorylation, Protein Kinases, Signal Transduction

Is Part Of

Publisher

Springer Science and Business Media LLC
Sponsorship
Medical Research Council (G1002610)
Academy of Medical Sciences (unknown)
Cambridge University Hospitals NHS Foundation Trust (CUH) (3819-1617-14)
Addenbrooke's Charitable Trust (ACT) (13/17 B(v) 900908/9980)
Medical Research Council (MR/R009120/1)
Medical Research Council (G0601840)
Wellcome Trust (100140/Z/12/Z)
Wellcome Trust (093026/Z/10/Z)