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Aging modulated by the Drosophila insulin receptor through distinct structure-defined mechanisms
Mutations of the Drosophila melanogaster insulin/IGF signaling system slow aging, while also affecting growth and reproduction. To understand this pleiotropy, we produced an allelic series of single codon substitutions in the Drosophila insulin receptor, InR. We generated InR substitutions using hom...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045697/ https://www.ncbi.nlm.nih.gov/pubmed/33724413 http://dx.doi.org/10.1093/genetics/iyaa037 |
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author | Yamamoto, Rochele Palmer, Michael Koski, Helen Curtis-Joseph, Noelle Tatar, Marc |
author_facet | Yamamoto, Rochele Palmer, Michael Koski, Helen Curtis-Joseph, Noelle Tatar, Marc |
author_sort | Yamamoto, Rochele |
collection | PubMed |
description | Mutations of the Drosophila melanogaster insulin/IGF signaling system slow aging, while also affecting growth and reproduction. To understand this pleiotropy, we produced an allelic series of single codon substitutions in the Drosophila insulin receptor, InR. We generated InR substitutions using homologous recombination and related each to emerging models of receptor tyrosine kinase structure and function. Three mutations when combined as trans-heterozygotes extended lifespan while retarding growth and fecundity. These genotypes reduced insulin-stimulated Akt phosphorylation, suggesting they impede kinase catalytic domain function. Among these genotypes, longevity was negatively correlated with egg production, consistent with life-history trade-off theory. In contrast, one mutation (InR(353)) was located in the kinase insert domain, a poorly characterized element found in all receptor tyrosine kinases. Remarkably, wild-type heterozygotes with InR(353) robustly extended lifespan without affecting growth or reproduction and retained capacity to fully phosphorylate Akt. The Drosophila insulin receptor kinase insert domain contains a previously unrecognized SH2 binding motif. We propose the kinase insert domain interacts with SH2-associated adapter proteins to affect aging through mechanisms that retain insulin sensitivity and are independent of reproduction. |
format | Online Article Text |
id | pubmed-8045697 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-80456972021-04-19 Aging modulated by the Drosophila insulin receptor through distinct structure-defined mechanisms Yamamoto, Rochele Palmer, Michael Koski, Helen Curtis-Joseph, Noelle Tatar, Marc Genetics Investigation Mutations of the Drosophila melanogaster insulin/IGF signaling system slow aging, while also affecting growth and reproduction. To understand this pleiotropy, we produced an allelic series of single codon substitutions in the Drosophila insulin receptor, InR. We generated InR substitutions using homologous recombination and related each to emerging models of receptor tyrosine kinase structure and function. Three mutations when combined as trans-heterozygotes extended lifespan while retarding growth and fecundity. These genotypes reduced insulin-stimulated Akt phosphorylation, suggesting they impede kinase catalytic domain function. Among these genotypes, longevity was negatively correlated with egg production, consistent with life-history trade-off theory. In contrast, one mutation (InR(353)) was located in the kinase insert domain, a poorly characterized element found in all receptor tyrosine kinases. Remarkably, wild-type heterozygotes with InR(353) robustly extended lifespan without affecting growth or reproduction and retained capacity to fully phosphorylate Akt. The Drosophila insulin receptor kinase insert domain contains a previously unrecognized SH2 binding motif. We propose the kinase insert domain interacts with SH2-associated adapter proteins to affect aging through mechanisms that retain insulin sensitivity and are independent of reproduction. Oxford University Press 2021-01-05 /pmc/articles/PMC8045697/ /pubmed/33724413 http://dx.doi.org/10.1093/genetics/iyaa037 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of Genetics Society of America. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Investigation Yamamoto, Rochele Palmer, Michael Koski, Helen Curtis-Joseph, Noelle Tatar, Marc Aging modulated by the Drosophila insulin receptor through distinct structure-defined mechanisms |
title | Aging modulated by the Drosophila insulin receptor through distinct structure-defined mechanisms |
title_full | Aging modulated by the Drosophila insulin receptor through distinct structure-defined mechanisms |
title_fullStr | Aging modulated by the Drosophila insulin receptor through distinct structure-defined mechanisms |
title_full_unstemmed | Aging modulated by the Drosophila insulin receptor through distinct structure-defined mechanisms |
title_short | Aging modulated by the Drosophila insulin receptor through distinct structure-defined mechanisms |
title_sort | aging modulated by the drosophila insulin receptor through distinct structure-defined mechanisms |
topic | Investigation |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045697/ https://www.ncbi.nlm.nih.gov/pubmed/33724413 http://dx.doi.org/10.1093/genetics/iyaa037 |
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