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Alternative AKT2 splicing produces protein lacking the hydrophobic motif regulatory region

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 in...

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Autores principales: Plotz, Guido, Lopez-Garcia, Laura A., Brieger, Angela, Zeuzem, Stefan, Biondi, Ricardo M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703976/
https://www.ncbi.nlm.nih.gov/pubmed/33253205
http://dx.doi.org/10.1371/journal.pone.0242819
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author Plotz, Guido
Lopez-Garcia, Laura A.
Brieger, Angela
Zeuzem, Stefan
Biondi, Ricardo M.
author_facet Plotz, Guido
Lopez-Garcia, Laura A.
Brieger, Angela
Zeuzem, Stefan
Biondi, Ricardo M.
author_sort Plotz, Guido
collection PubMed
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.
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spelling pubmed-77039762020-12-03 Alternative AKT2 splicing produces protein lacking the hydrophobic motif regulatory region Plotz, Guido Lopez-Garcia, Laura A. Brieger, Angela Zeuzem, Stefan Biondi, Ricardo M. PLoS One Research Article 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. Public Library of Science 2020-11-30 /pmc/articles/PMC7703976/ /pubmed/33253205 http://dx.doi.org/10.1371/journal.pone.0242819 Text en © 2020 Plotz et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Plotz, Guido
Lopez-Garcia, Laura A.
Brieger, Angela
Zeuzem, Stefan
Biondi, Ricardo M.
Alternative AKT2 splicing produces protein lacking the hydrophobic motif regulatory region
title 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_short Alternative AKT2 splicing produces protein lacking the hydrophobic motif regulatory region
title_sort alternative akt2 splicing produces protein lacking the hydrophobic motif regulatory region
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703976/
https://www.ncbi.nlm.nih.gov/pubmed/33253205
http://dx.doi.org/10.1371/journal.pone.0242819
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