Alternative AKT2 splicing produces protein lacking the hydrophobic motif regulatory region

Autores
Plotz, Guido; Lopez-Garcia, Laura A.; Brieger, Angela; Zeuzem, Stefan; Biondi, Ricardo Miguel
Año de publicación
2020
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Three AKT serine/threonine kinase isoforms (AKT1/AKT2/AKT3) mediate proliferation, metabolism, differentiation and anti-apoptotic signals. AKT isoforms are activated downstream of PI3-kinase and also by PI3-kinase independent mechanisms. Mutations in the lipid phosphatase PTEN and PI3-kinase that increase PIP3 levels increase AKT signaling in a large proportion of human cancers. AKT and other AGC kinases possess a regulatory mechanism that relies on a conserved hydrophobic motif (HM) C-terminal to the catalytic core. In AKT, the HM is contiguous to the serine 473 and two other newly discovered (serine 477 and tyrosine 479) regulatory phosphorylation sites. In AKT genes, this regulatory HM region is encoded in the final exon. We identified a splice variant of AKT2 (AKT2-13a), which contains an alternative final exon and lacks the HM regulatory site. We validated the presence of mRNA for this AKT2-13a splice variant in different tissues, and the presence of AKT2-13a protein in extracts from HEK293 cells. When overexpressed in HEK293 cells, AKT2-13a is phosphorylated at the activation loop and at the zipper/turn motif phosphorylation sites but has reduced specific activity. Analysis of the human transcriptome corresponding to other AGC kinases revealed that all three AKT isoforms express alternative transcripts lacking the HM regulatory motif, which was not the case for SGK1-3, S6K1-2, and classical, novel and atypical PKC isoforms. The transcripts of splice variants of Akt1-3 excluding the HM regulatory region could lead to expression of deregulated forms of AKT.
Fil: Plotz, Guido. Klinikum Und Fachbereich Medizin Johann Wolfgang Goethe-universität Frankfurt Am Main; Alemania
Fil: Lopez-Garcia, Laura A.. Goethe Universitat Frankfurt; Alemania
Fil: Brieger, Angela. Klinikum Und Fachbereich Medizin Johann Wolfgang Goethe-universität Frankfurt Am Main; Alemania
Fil: Zeuzem, Stefan. Klinikum Und Fachbereich Medizin Johann Wolfgang Goethe-universität Frankfurt Am Main; Alemania
Fil: Biondi, Ricardo Miguel. German Cancer Research Center; Alemania. Klinikum Und Fachbereich Medizin Johann Wolfgang Goethe-universität Frankfurt Am Main; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina
Materia
Akt
PKB
PIF-pocket
splicing
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/143292
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/143292
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Alternative AKT2 splicing produces protein lacking the hydrophobic motif regulatory regionPlotz, GuidoLopez-Garcia, Laura A.Brieger, AngelaZeuzem, StefanBiondi, Ricardo MiguelAktPKBPIF-pocketsplicinghttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Three AKT serine/threonine kinase isoforms (AKT1/AKT2/AKT3) mediate proliferation, metabolism, differentiation and anti-apoptotic signals. AKT isoforms are activated downstream of PI3-kinase and also by PI3-kinase independent mechanisms. Mutations in the lipid phosphatase PTEN and PI3-kinase that increase PIP3 levels increase AKT signaling in a large proportion of human cancers. AKT and other AGC kinases possess a regulatory mechanism that relies on a conserved hydrophobic motif (HM) C-terminal to the catalytic core. In AKT, the HM is contiguous to the serine 473 and two other newly discovered (serine 477 and tyrosine 479) regulatory phosphorylation sites. In AKT genes, this regulatory HM region is encoded in the final exon. We identified a splice variant of AKT2 (AKT2-13a), which contains an alternative final exon and lacks the HM regulatory site. We validated the presence of mRNA for this AKT2-13a splice variant in different tissues, and the presence of AKT2-13a protein in extracts from HEK293 cells. When overexpressed in HEK293 cells, AKT2-13a is phosphorylated at the activation loop and at the zipper/turn motif phosphorylation sites but has reduced specific activity. Analysis of the human transcriptome corresponding to other AGC kinases revealed that all three AKT isoforms express alternative transcripts lacking the HM regulatory motif, which was not the case for SGK1-3, S6K1-2, and classical, novel and atypical PKC isoforms. The transcripts of splice variants of Akt1-3 excluding the HM regulatory region could lead to expression of deregulated forms of AKT.Fil: Plotz, Guido. Klinikum Und Fachbereich Medizin Johann Wolfgang Goethe-universität Frankfurt Am Main; AlemaniaFil: Lopez-Garcia, Laura A.. Goethe Universitat Frankfurt; AlemaniaFil: Brieger, Angela. Klinikum Und Fachbereich Medizin Johann Wolfgang Goethe-universität Frankfurt Am Main; AlemaniaFil: Zeuzem, Stefan. Klinikum Und Fachbereich Medizin Johann Wolfgang Goethe-universität Frankfurt Am Main; AlemaniaFil: Biondi, Ricardo Miguel. German Cancer Research Center; Alemania. Klinikum Und Fachbereich Medizin Johann Wolfgang Goethe-universität Frankfurt Am Main; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; ArgentinaPublic Library of Science2020-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/143292Plotz, Guido; Lopez-Garcia, Laura A.; Brieger, Angela; Zeuzem, Stefan; Biondi, Ricardo Miguel; Alternative AKT2 splicing produces protein lacking the hydrophobic motif regulatory region; Public Library of Science; Plos One; 15; 11; 11-2020; 1-131932-6203CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pone.0242819info:eu-repo/semantics/altIdentifier/url/https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242819info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:45:53Zoai:ri.conicet.gov.ar:11336/143292instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 09:45:54.017CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Alternative AKT2 splicing produces protein lacking the hydrophobic motif regulatory region
title Alternative AKT2 splicing produces protein lacking the hydrophobic motif regulatory region
spellingShingle Alternative AKT2 splicing produces protein lacking the hydrophobic motif regulatory region
Plotz, Guido
Akt
PKB
PIF-pocket
splicing
title_short Alternative AKT2 splicing produces protein lacking the hydrophobic motif regulatory region
title_full Alternative AKT2 splicing produces protein lacking the hydrophobic motif regulatory region
title_fullStr Alternative AKT2 splicing produces protein lacking the hydrophobic motif regulatory region
title_full_unstemmed Alternative AKT2 splicing produces protein lacking the hydrophobic motif regulatory region
title_sort Alternative AKT2 splicing produces protein lacking the hydrophobic motif regulatory region
dc.creator.none.fl_str_mv Plotz, Guido
Lopez-Garcia, Laura A.
Brieger, Angela
Zeuzem, Stefan
Biondi, Ricardo Miguel
author Plotz, Guido
author_facet Plotz, Guido
Lopez-Garcia, Laura A.
Brieger, Angela
Zeuzem, Stefan
Biondi, Ricardo Miguel
author_role author
author2 Lopez-Garcia, Laura A.
Brieger, Angela
Zeuzem, Stefan
Biondi, Ricardo Miguel
author2_role author
author
author
author
dc.subject.none.fl_str_mv Akt
PKB
PIF-pocket
splicing
topic Akt
PKB
PIF-pocket
splicing
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Three AKT serine/threonine kinase isoforms (AKT1/AKT2/AKT3) mediate proliferation, metabolism, differentiation and anti-apoptotic signals. AKT isoforms are activated downstream of PI3-kinase and also by PI3-kinase independent mechanisms. Mutations in the lipid phosphatase PTEN and PI3-kinase that increase PIP3 levels increase AKT signaling in a large proportion of human cancers. AKT and other AGC kinases possess a regulatory mechanism that relies on a conserved hydrophobic motif (HM) C-terminal to the catalytic core. In AKT, the HM is contiguous to the serine 473 and two other newly discovered (serine 477 and tyrosine 479) regulatory phosphorylation sites. In AKT genes, this regulatory HM region is encoded in the final exon. We identified a splice variant of AKT2 (AKT2-13a), which contains an alternative final exon and lacks the HM regulatory site. We validated the presence of mRNA for this AKT2-13a splice variant in different tissues, and the presence of AKT2-13a protein in extracts from HEK293 cells. When overexpressed in HEK293 cells, AKT2-13a is phosphorylated at the activation loop and at the zipper/turn motif phosphorylation sites but has reduced specific activity. Analysis of the human transcriptome corresponding to other AGC kinases revealed that all three AKT isoforms express alternative transcripts lacking the HM regulatory motif, which was not the case for SGK1-3, S6K1-2, and classical, novel and atypical PKC isoforms. The transcripts of splice variants of Akt1-3 excluding the HM regulatory region could lead to expression of deregulated forms of AKT.
Fil: Plotz, Guido. Klinikum Und Fachbereich Medizin Johann Wolfgang Goethe-universität Frankfurt Am Main; Alemania
Fil: Lopez-Garcia, Laura A.. Goethe Universitat Frankfurt; Alemania
Fil: Brieger, Angela. Klinikum Und Fachbereich Medizin Johann Wolfgang Goethe-universität Frankfurt Am Main; Alemania
Fil: Zeuzem, Stefan. Klinikum Und Fachbereich Medizin Johann Wolfgang Goethe-universität Frankfurt Am Main; Alemania
Fil: Biondi, Ricardo Miguel. German Cancer Research Center; Alemania. Klinikum Und Fachbereich Medizin Johann Wolfgang Goethe-universität Frankfurt Am Main; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina
description Three AKT serine/threonine kinase isoforms (AKT1/AKT2/AKT3) mediate proliferation, metabolism, differentiation and anti-apoptotic signals. AKT isoforms are activated downstream of PI3-kinase and also by PI3-kinase independent mechanisms. Mutations in the lipid phosphatase PTEN and PI3-kinase that increase PIP3 levels increase AKT signaling in a large proportion of human cancers. AKT and other AGC kinases possess a regulatory mechanism that relies on a conserved hydrophobic motif (HM) C-terminal to the catalytic core. In AKT, the HM is contiguous to the serine 473 and two other newly discovered (serine 477 and tyrosine 479) regulatory phosphorylation sites. In AKT genes, this regulatory HM region is encoded in the final exon. We identified a splice variant of AKT2 (AKT2-13a), which contains an alternative final exon and lacks the HM regulatory site. We validated the presence of mRNA for this AKT2-13a splice variant in different tissues, and the presence of AKT2-13a protein in extracts from HEK293 cells. When overexpressed in HEK293 cells, AKT2-13a is phosphorylated at the activation loop and at the zipper/turn motif phosphorylation sites but has reduced specific activity. Analysis of the human transcriptome corresponding to other AGC kinases revealed that all three AKT isoforms express alternative transcripts lacking the HM regulatory motif, which was not the case for SGK1-3, S6K1-2, and classical, novel and atypical PKC isoforms. The transcripts of splice variants of Akt1-3 excluding the HM regulatory region could lead to expression of deregulated forms of AKT.
publishDate 2020
dc.date.none.fl_str_mv 2020-11
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/143292
Plotz, Guido; Lopez-Garcia, Laura A.; Brieger, Angela; Zeuzem, Stefan; Biondi, Ricardo Miguel; Alternative AKT2 splicing produces protein lacking the hydrophobic motif regulatory region; Public Library of Science; Plos One; 15; 11; 11-2020; 1-13
1932-6203
CONICET Digital
CONICET
url http://hdl.handle.net/11336/143292
identifier_str_mv Plotz, Guido; Lopez-Garcia, Laura A.; Brieger, Angela; Zeuzem, Stefan; Biondi, Ricardo Miguel; Alternative AKT2 splicing produces protein lacking the hydrophobic motif regulatory region; Public Library of Science; Plos One; 15; 11; 11-2020; 1-13
1932-6203
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1371/journal.pone.0242819
info:eu-repo/semantics/altIdentifier/url/https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242819
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Public Library of Science
publisher.none.fl_str_mv Public Library of Science
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1842268760190222336
score 13.13397

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