Quadruple and Truncated MEK3 Mutants Identified from Acute Lymphoblastic Leukemia Promote Degradation and Enhance Proliferation

Compared to other ethnicities, Hispanic children incur the highest rates of leukemia, and most cases are diagnosed as Acute Lymphoblastic Leukemia (ALL). Despite improved treatment and survival for ALL, disproportionate health outcomes in Hispanics persist. Thus, it is essential to identify oncogeni...

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Autores principales:	Yoshira M. Ayala-Marin, Alice H. Grant, Georgialina Rodriguez, Robert A. Kirken
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	MAP2K3 MEK3 MAPK p38 ALL Hispanic protein degradation Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/bf0749e437154f87ad4cdf343e2324a3
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spelling	oai:doaj.org-article:bf0749e437154f87ad4cdf343e2324a32021-11-25T17:54:23ZQuadruple and Truncated MEK3 Mutants Identified from Acute Lymphoblastic Leukemia Promote Degradation and Enhance Proliferation10.3390/ijms2222122101422-00671661-6596https://doaj.org/article/bf0749e437154f87ad4cdf343e2324a32021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12210https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Compared to other ethnicities, Hispanic children incur the highest rates of leukemia, and most cases are diagnosed as Acute Lymphoblastic Leukemia (ALL). Despite improved treatment and survival for ALL, disproportionate health outcomes in Hispanics persist. Thus, it is essential to identify oncogenic mutations within this demographic to aid in the development of new strategies to diagnose and treat ALL. Using whole-exome sequencing, five single nucleotide polymorphisms within mitogen-activated protein kinase 3 (MAP2K3) were identified in an ALL cancer patient library from the U.S./Mexico border. MAP2K3 R26T and P11T are located near the substrate-binding site, while R65L and R67W localized to the kinase domain. Truncated-MAP2K3 mutant Q73* was also identified. Transfection in HEK293 cells showed that the quadruple-MEK3 mutant (4M-MEK3) impacted protein stability, inducing degradation and reducing expression. The expression of 4M-MEK3 could be rescued by cysteine/serine protease inhibition, and proteasomal degradation of truncated-MEK3 occurred in a ubiquitin-independent manner. MEK3 mutants displayed reduced auto-phosphorylation and enzymatic activity, as seen by decreases in p38 phosphorylation. Furthermore, uncoupling of the MEK3/p38 signaling pathway resulted in less suppressive activity on HEK293 cell viability. Thus, disruption of MEK3 activation may promote proliferative signals in ALL. These findings suggest that MEK3 represents a potential therapeutic target for treating ALL.Yoshira M. Ayala-MarinAlice H. GrantGeorgialina RodriguezRobert A. KirkenMDPI AGarticleMAP2K3MEK3MAPK p38ALLHispanicprotein degradationBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12210, p 12210 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	MAP2K3 MEK3 MAPK p38 ALL Hispanic protein degradation Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	MAP2K3 MEK3 MAPK p38 ALL Hispanic protein degradation Biology (General) QH301-705.5 Chemistry QD1-999 Yoshira M. Ayala-Marin Alice H. Grant Georgialina Rodriguez Robert A. Kirken Quadruple and Truncated MEK3 Mutants Identified from Acute Lymphoblastic Leukemia Promote Degradation and Enhance Proliferation
description	Compared to other ethnicities, Hispanic children incur the highest rates of leukemia, and most cases are diagnosed as Acute Lymphoblastic Leukemia (ALL). Despite improved treatment and survival for ALL, disproportionate health outcomes in Hispanics persist. Thus, it is essential to identify oncogenic mutations within this demographic to aid in the development of new strategies to diagnose and treat ALL. Using whole-exome sequencing, five single nucleotide polymorphisms within mitogen-activated protein kinase 3 (MAP2K3) were identified in an ALL cancer patient library from the U.S./Mexico border. MAP2K3 R26T and P11T are located near the substrate-binding site, while R65L and R67W localized to the kinase domain. Truncated-MAP2K3 mutant Q73* was also identified. Transfection in HEK293 cells showed that the quadruple-MEK3 mutant (4M-MEK3) impacted protein stability, inducing degradation and reducing expression. The expression of 4M-MEK3 could be rescued by cysteine/serine protease inhibition, and proteasomal degradation of truncated-MEK3 occurred in a ubiquitin-independent manner. MEK3 mutants displayed reduced auto-phosphorylation and enzymatic activity, as seen by decreases in p38 phosphorylation. Furthermore, uncoupling of the MEK3/p38 signaling pathway resulted in less suppressive activity on HEK293 cell viability. Thus, disruption of MEK3 activation may promote proliferative signals in ALL. These findings suggest that MEK3 represents a potential therapeutic target for treating ALL.
format	article
author	Yoshira M. Ayala-Marin Alice H. Grant Georgialina Rodriguez Robert A. Kirken
author_facet	Yoshira M. Ayala-Marin Alice H. Grant Georgialina Rodriguez Robert A. Kirken
author_sort	Yoshira M. Ayala-Marin
title	Quadruple and Truncated MEK3 Mutants Identified from Acute Lymphoblastic Leukemia Promote Degradation and Enhance Proliferation
title_short	Quadruple and Truncated MEK3 Mutants Identified from Acute Lymphoblastic Leukemia Promote Degradation and Enhance Proliferation
title_full	Quadruple and Truncated MEK3 Mutants Identified from Acute Lymphoblastic Leukemia Promote Degradation and Enhance Proliferation
title_fullStr	Quadruple and Truncated MEK3 Mutants Identified from Acute Lymphoblastic Leukemia Promote Degradation and Enhance Proliferation
title_full_unstemmed	Quadruple and Truncated MEK3 Mutants Identified from Acute Lymphoblastic Leukemia Promote Degradation and Enhance Proliferation
title_sort	quadruple and truncated mek3 mutants identified from acute lymphoblastic leukemia promote degradation and enhance proliferation
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/bf0749e437154f87ad4cdf343e2324a3
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Quadruple and Truncated MEK3 Mutants Identified from Acute Lymphoblastic Leukemia Promote Degradation and Enhance Proliferation

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