Cargando…
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...
Autores principales: | , , , , , |
---|---|
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 |
_version_ | 1783303866165493760 |
---|---|
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. |
format | Online Article Text |
id | pubmed-5835844 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT cairnsjunmei differentialrolesoferrfi1inegfrandaktpathwayregulationaffectcancerproliferation AT fridleybrookel differentialrolesoferrfi1inegfrandaktpathwayregulationaffectcancerproliferation AT jenkinsgregoryd differentialrolesoferrfi1inegfrandaktpathwayregulationaffectcancerproliferation AT zhuangyongxian differentialrolesoferrfi1inegfrandaktpathwayregulationaffectcancerproliferation AT yujia differentialrolesoferrfi1inegfrandaktpathwayregulationaffectcancerproliferation AT wangliewei differentialrolesoferrfi1inegfrandaktpathwayregulationaffectcancerproliferation |