BRAFV600E negatively regulates the AKT pathway in melanoma cell lines.

Cross-feedback activation of MAPK and AKT pathways is implicated as a resistance mechanism for cancer therapeutic agents targeting either RAF/MEK or PI3K/AKT/mTOR. It is thus important to have a better understanding of the molecular resistance mechanisms to improve patient survival benefit from thes...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Brenden Chen, Christine Tardell, Brian Higgins, Kathryn Packman, John F Boylan, Huifeng Niu
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f977105d31fa4f8f9f44e379c7007545
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:f977105d31fa4f8f9f44e379c7007545
record_format	dspace
spelling	oai:doaj.org-article:f977105d31fa4f8f9f44e379c70075452021-11-18T07:09:42ZBRAFV600E negatively regulates the AKT pathway in melanoma cell lines.1932-620310.1371/journal.pone.0042598https://doaj.org/article/f977105d31fa4f8f9f44e379c70075452012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22880048/?tool=EBIhttps://doaj.org/toc/1932-6203Cross-feedback activation of MAPK and AKT pathways is implicated as a resistance mechanism for cancer therapeutic agents targeting either RAF/MEK or PI3K/AKT/mTOR. It is thus important to have a better understanding of the molecular resistance mechanisms to improve patient survival benefit from these agents. Here we show that BRAFV600E is a negative regulator of the AKT pathway. Expression of BRAFV600E in NIH3T3 cells significantly suppresses MEK inhibitor (RG7167) or mTORC1 inhibitor (rapamycin) induced AKT phosphorylation (pAKT) and downstream signal activation. Treatment-induced pAKT elevation is found in BRAF wild type melanoma cells but not in a subset of melanoma cell lines harboring BRAFV600E. Knock-down of BRAFV600E in these melanoma cells elevates basal pAKT and downstream signals, whereas knock-down of CRAF, MEK1/2 or ERK1/2 or treatment with a BRAF inhibitor have no impact on pAKT. Mechanistically, we show that BRAFV600E interacts with rictor complex (mTORC2) and regulates pAKT through mTORC2. BRAFV600E is identified in mTORC2 after immunoprecipitation of rictor. Knock-down of rictor abrogates BRAFV600E depletion induced pAKT. Knock-down of BRAFV600E enhances cellular enzyme activity of mTORC2. Aberrant activation of AKT pathway by PTEN loss appears to override the negative impact of BRAFV600E on pAKT. Taken together, our findings suggest that in a subset of BRAFV600E melanoma cells, BRAFV600E negatively regulates AKT pathway in a rictor-dependent, MEK/ERK and BRAF kinase-independent manner. Our study reveals a novel molecular mechanism underlying the regulation of feedback loops between the MAPK and AKT pathways.Brenden ChenChristine TardellBrian HigginsKathryn PackmanJohn F BoylanHuifeng NiuPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 8, p e42598 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Brenden Chen Christine Tardell Brian Higgins Kathryn Packman John F Boylan Huifeng Niu BRAFV600E negatively regulates the AKT pathway in melanoma cell lines.
description	Cross-feedback activation of MAPK and AKT pathways is implicated as a resistance mechanism for cancer therapeutic agents targeting either RAF/MEK or PI3K/AKT/mTOR. It is thus important to have a better understanding of the molecular resistance mechanisms to improve patient survival benefit from these agents. Here we show that BRAFV600E is a negative regulator of the AKT pathway. Expression of BRAFV600E in NIH3T3 cells significantly suppresses MEK inhibitor (RG7167) or mTORC1 inhibitor (rapamycin) induced AKT phosphorylation (pAKT) and downstream signal activation. Treatment-induced pAKT elevation is found in BRAF wild type melanoma cells but not in a subset of melanoma cell lines harboring BRAFV600E. Knock-down of BRAFV600E in these melanoma cells elevates basal pAKT and downstream signals, whereas knock-down of CRAF, MEK1/2 or ERK1/2 or treatment with a BRAF inhibitor have no impact on pAKT. Mechanistically, we show that BRAFV600E interacts with rictor complex (mTORC2) and regulates pAKT through mTORC2. BRAFV600E is identified in mTORC2 after immunoprecipitation of rictor. Knock-down of rictor abrogates BRAFV600E depletion induced pAKT. Knock-down of BRAFV600E enhances cellular enzyme activity of mTORC2. Aberrant activation of AKT pathway by PTEN loss appears to override the negative impact of BRAFV600E on pAKT. Taken together, our findings suggest that in a subset of BRAFV600E melanoma cells, BRAFV600E negatively regulates AKT pathway in a rictor-dependent, MEK/ERK and BRAF kinase-independent manner. Our study reveals a novel molecular mechanism underlying the regulation of feedback loops between the MAPK and AKT pathways.
format	article
author	Brenden Chen Christine Tardell Brian Higgins Kathryn Packman John F Boylan Huifeng Niu
author_facet	Brenden Chen Christine Tardell Brian Higgins Kathryn Packman John F Boylan Huifeng Niu
author_sort	Brenden Chen
title	BRAFV600E negatively regulates the AKT pathway in melanoma cell lines.
title_short	BRAFV600E negatively regulates the AKT pathway in melanoma cell lines.
title_full	BRAFV600E negatively regulates the AKT pathway in melanoma cell lines.
title_fullStr	BRAFV600E negatively regulates the AKT pathway in melanoma cell lines.
title_full_unstemmed	BRAFV600E negatively regulates the AKT pathway in melanoma cell lines.
title_sort	brafv600e negatively regulates the akt pathway in melanoma cell lines.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/f977105d31fa4f8f9f44e379c7007545
work_keys_str_mv	AT brendenchen brafv600enegativelyregulatestheaktpathwayinmelanomacelllines AT christinetardell brafv600enegativelyregulatestheaktpathwayinmelanomacelllines AT brianhiggins brafv600enegativelyregulatestheaktpathwayinmelanomacelllines AT kathrynpackman brafv600enegativelyregulatestheaktpathwayinmelanomacelllines AT johnfboylan brafv600enegativelyregulatestheaktpathwayinmelanomacelllines AT huifengniu brafv600enegativelyregulatestheaktpathwayinmelanomacelllines
_version_	1718423891154567168

BRAFV600E negatively regulates the AKT pathway in melanoma cell lines.

Ejemplares similares