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TGF-β promotes PI3K-AKT signaling and prostate cancer cell migration through the TRAF6-mediated ubiquitylation of p85α
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
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2017 (English)In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 10, no 486, eaal4186Article in journal (Refereed) Published
Abstract [en]

Transforming growth factor–β (TGF-β) is a pluripotent cytokine that regulates cell fate and plasticity in normal tissues and tumors. The multifunctional cellular responses evoked by TGF-β are mediated by the canonical SMAD pathway and by noncanonical pathways, including mitogen-activated protein kinase (MAPK) pathways and the phosphatidylinositol 3′-kinase (PI3K)–protein kinase B (AKT) pathway. We found that TGF-β activated PI3K in a manner dependent on the activity of the E3 ubiquitin ligase tumor necrosis factor receptor–associated factor 6 (TRAF6). TRAF6 polyubiquitylated the PI3K regulatory subunit p85α and promoted the formation of a complex between the TGF-β type I receptor (TβRI) and p85α, which led to the activation of PI3K and AKT. Lys63-linked polyubiquitylation of p85α on Lys513 and Lys519 in the iSH2 (inter–Src homology 2) domain was required for TGF-β–induced activation of PI3K-AKT signaling and cell motility in prostate cancer cells and activated macrophages. Unlike the activation of SMAD pathways, the TRAF6-mediated activation of PI3K and AKT was not dependent on the kinase activity of TβRI. In situ proximity ligation assays revealed that polyubiquitylation of p85α was evident in aggressive prostate cancer tissues. Thus, our data reveal a molecular mechanism by which TGF-β activates the PI3K-AKT pathway to drive cell migration.

Place, publisher, year, edition, pages
American Association for the Advancement of Science , 2017. Vol. 10, no 486, eaal4186
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-137787DOI: 10.1126/scisignal.aal4186ISI: 000404615300002PubMedID: 28676490OAI: oai:DiVA.org:umu-137787DiVA: diva2:1128689
Note

TGF-beta promotes PI3K-AKT signaling and prostate cancer cell migration through the TRAF6-mediated ubiquitylation of p85 alpha

Available from: 2017-07-27 Created: 2017-07-27 Last updated: 2017-07-27Bibliographically approved

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CiteExportLink to record
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Cite
Citation style
  • apa
  • harvard1
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  • modern-language-association-8th-edition
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