Alternative AKT2 splicing produces protein lacking the hydrophobic motif regulatory region.

Autor: Plotz G; Biomedizinisches Forschungslabor, Medizinische Klinik 1, Universitätsklinik Frankfurt, Frankfurt, Germany., Lopez-Garcia LA; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany., Brieger A; Biomedizinisches Forschungslabor, Medizinische Klinik 1, Universitätsklinik Frankfurt, Frankfurt, Germany., Zeuzem S; Biomedizinisches Forschungslabor, Medizinische Klinik 1, Universitätsklinik Frankfurt, Frankfurt, Germany., Biondi RM; Biomedizinisches Forschungslabor, Medizinische Klinik 1, Universitätsklinik Frankfurt, Frankfurt, Germany.; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.; Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA)-CONICET-Partner Institute of the Max Planck Society, Buenos Aires, Argentina.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2020 Nov 30; Vol. 15 (11), pp. e0242819. Date of Electronic Publication: 2020 Nov 30 (Print Publication: 2020).
DOI: 10.1371/journal.pone.0242819
Abstrakt: 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.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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