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The unique non-catalytic C-terminus of p37delta-PI3K adds proliferative properties in vitro and in vivo
University of Skövde, School of Bioscience. University of Skövde, The Systems Biology Research Centre. Department of Medical and Clinical Genetics, Gothenburg University, Gothenburg, Sweden. (Tumörbiologi, Tumor Biology)ORCID iD: 0000-0001-8962-0860
University of Skövde, The Systems Biology Research Centre.
University of Skövde, The Systems Biology Research Centre.
Department of General Surgery, Gothenburg University, Gothenburg, Sweden.
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 5, e0127497Article in journal (Refereed) Published
Abstract [en]

The PI3K/Akt pathway is central for numerous cellular functions and is frequently deregulated in human cancers. The catalytic subunits of PI3K, p110, are thought to have a potential oncogenic function, and the regulatory subunit p85 exerts tumor suppressor properties. The fruit fly, Drosophila melanogaster, is a highly suitable system to investigate PI3K signaling, expressing one catalytic, Dp110, and one regulatory subunit, Dp60, and both show strong homology with the human PI3K proteins p110 and p85. We recently showed that p37δ, an alternatively spliced product of human PI3K p110δ, displayed strong proliferation-promoting properties despite lacking the catalytic domain completely. Here we functionally evaluate the different domains of human p37δ in Drosophila. The N-terminal region of Dp110 alone promotes cell proliferation, and we show that the unique C-terminal region of human p37δ further enhances these proliferative properties, both when expressed in Drosophila, and in human HEK-293 cells. Surprisingly, although the N-terminal region of Dp110 and the C-terminal region of p37δ both display proliferative effects, over-expression of full length Dp110 or the N-terminal part of Dp110 decreases survival in Drosophila, whereas the unique C-terminal region of p37δ prevents this effect. Furthermore, we found that the N-terminal region of the catalytic subunit of PI3K p110, including only the Dp60 (p85)-binding domain and a minor part of the Ras binding domain, rescues phenotypes with severely impaired development caused by Dp60 over-expression in Drosophila, possibly by regulating the levels of Dp60, and also by increasing the levels of phosphorylated Akt. Our results indicate a novel kinase-independent function of the PI3K catalytic subunit.

Place, publisher, year, edition, pages
PLOS , 2015. Vol. 10, no 5, e0127497
National Category
Medical Genetics Cell and Molecular Biology
Research subject
Medical sciences
Identifiers
URN: urn:nbn:se:his:diva-11448DOI: 10.1371/journal.pone.0127497ISI: 000355319400038PubMedID: 26024481Scopus ID: 2-s2.0-84932614925OAI: oai:DiVA.org:his-11448DiVA: diva2:849358
Funder
Swedish Childhood Cancer FoundationKnowledge FoundationSwedish Research Council
Available from: 2015-08-28 Created: 2015-08-28 Last updated: 2015-12-01Bibliographically approved

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