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Differential roles of ERRFI1 in EGFR and AKT pathway regulation affect cancer proliferation

AKT signaling is modulated by a complex network of regulatory proteins and is commonly deregulated in cancer. Here, we present a dual mechanism of AKT regulation by the ERBB receptor feedback inhibitor 1 (ERRFI1). We show that in cells expressing high levels of EGFR, ERRF1 inhibits growth and enhanc...

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Autores principales: Cairns, Junmei, Fridley, Brooke L, Jenkins, Gregory D, Zhuang, Yongxian, Yu, Jia, Wang, Liewei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835844/
https://www.ncbi.nlm.nih.gov/pubmed/29335246
http://dx.doi.org/10.15252/embr.201744767
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author Cairns, Junmei
Fridley, Brooke L
Jenkins, Gregory D
Zhuang, Yongxian
Yu, Jia
Wang, Liewei
author_facet Cairns, Junmei
Fridley, Brooke L
Jenkins, Gregory D
Zhuang, Yongxian
Yu, Jia
Wang, Liewei
author_sort Cairns, Junmei
collection PubMed
description AKT signaling is modulated by a complex network of regulatory proteins and is commonly deregulated in cancer. Here, we present a dual mechanism of AKT regulation by the ERBB receptor feedback inhibitor 1 (ERRFI1). We show that in cells expressing high levels of EGFR, ERRF1 inhibits growth and enhances responses to chemotherapy. This is mediated in part through the negative regulation of AKT signaling by direct ERRFI1‐dependent inhibition of EGFR. In cells expressing low levels of EGFR, ERRFI1 positively modulates AKT signaling by interfering with the interaction of the inactivating phosphatase PHLPP with AKT, thereby promoting cell growth and chemotherapy desensitization. These observations broaden our understanding of chemotherapy response and have important implications for the selection of targeted therapies in a cell context‐dependent manner. EGFR inhibition can only sensitize EGFR‐high cells for chemotherapy, while AKT inhibition increases chemosensitivity in EGFR‐low cells. By understanding these mechanisms, we can take advantage of the cellular context to individualize antineoplastic therapy. Finally, our data also suggest targeting of EFFRI1 in EGFR‐low cancer as a promising therapeutic approach.
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spelling pubmed-58358442018-03-14 Differential roles of ERRFI1 in EGFR and AKT pathway regulation affect cancer proliferation Cairns, Junmei Fridley, Brooke L Jenkins, Gregory D Zhuang, Yongxian Yu, Jia Wang, Liewei EMBO Rep Articles AKT signaling is modulated by a complex network of regulatory proteins and is commonly deregulated in cancer. Here, we present a dual mechanism of AKT regulation by the ERBB receptor feedback inhibitor 1 (ERRFI1). We show that in cells expressing high levels of EGFR, ERRF1 inhibits growth and enhances responses to chemotherapy. This is mediated in part through the negative regulation of AKT signaling by direct ERRFI1‐dependent inhibition of EGFR. In cells expressing low levels of EGFR, ERRFI1 positively modulates AKT signaling by interfering with the interaction of the inactivating phosphatase PHLPP with AKT, thereby promoting cell growth and chemotherapy desensitization. These observations broaden our understanding of chemotherapy response and have important implications for the selection of targeted therapies in a cell context‐dependent manner. EGFR inhibition can only sensitize EGFR‐high cells for chemotherapy, while AKT inhibition increases chemosensitivity in EGFR‐low cells. By understanding these mechanisms, we can take advantage of the cellular context to individualize antineoplastic therapy. Finally, our data also suggest targeting of EFFRI1 in EGFR‐low cancer as a promising therapeutic approach. John Wiley and Sons Inc. 2018-01-15 2018-03 /pmc/articles/PMC5835844/ /pubmed/29335246 http://dx.doi.org/10.15252/embr.201744767 Text en © 2018 The Authors. Published under the terms of the CC BY NC ND 4.0 license This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Articles
Cairns, Junmei
Fridley, Brooke L
Jenkins, Gregory D
Zhuang, Yongxian
Yu, Jia
Wang, Liewei
Differential roles of ERRFI1 in EGFR and AKT pathway regulation affect cancer proliferation
title Differential roles of ERRFI1 in EGFR and AKT pathway regulation affect cancer proliferation
title_full Differential roles of ERRFI1 in EGFR and AKT pathway regulation affect cancer proliferation
title_fullStr Differential roles of ERRFI1 in EGFR and AKT pathway regulation affect cancer proliferation
title_full_unstemmed Differential roles of ERRFI1 in EGFR and AKT pathway regulation affect cancer proliferation
title_short Differential roles of ERRFI1 in EGFR and AKT pathway regulation affect cancer proliferation
title_sort differential roles of errfi1 in egfr and akt pathway regulation affect cancer proliferation
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835844/
https://www.ncbi.nlm.nih.gov/pubmed/29335246
http://dx.doi.org/10.15252/embr.201744767
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