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APPL proteins promote TGF beta-induced nuclear transport of the TGF beta type I receptor intracellular domain
Umea Univ, Med Biosci, Umea, Sweden..
Umea Univ, Med Biosci, Umea, Sweden..
Jilin Univ, Stomatol Hosp, Implant Ctr, Changchun 130023, Peoples R China..
Umea Univ, Med Biosci, Umea, Sweden..
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2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 1, 279-292 p.Article in journal (Refereed) PublishedText
Abstract [en]

The multifunctional cytokine transforming growth factor-beta (TGF beta) is produced by several types of cancers, including prostate cancer, and promote tumour progression in autocrine and paracrine manners. In response to ligand binding, the TGF beta type I receptor (T beta RI) activates Smad and non-Smad signalling pathways. The ubiquitin-ligase tumour necrosis factor receptor-associated factor 6 (TRAF6) was recently linked to regulate intramembrane proteolytic cleavage of the T beta RI in cancer cells. Subsequently, the intracellular domain (ICD) of T beta RI enters in an unknown manner into the nucleus, where it promotes the transcription of pro-invasive genes, such as MMP2 and MMP9. Here we show that the endocytic adaptor molecules APPL1 and APPL2 are required for TGF beta-induced nuclear translocation of T beta RI-ICD and for cancer cell invasiveness of human prostate and breast cancer cell lines. Moreover, APPL proteins were found to be expressed at high levels in aggressive prostate cancer tissues, and to be associated with T beta RI in a TRAF6-dependent manner. Our results suggest that the APPL-T beta RI complex promotes prostate tumour progression, and may serve as a prognostic marker.

Place, publisher, year, edition, pages
2016. Vol. 7, no 1, 279-292 p.
Keyword [en]
APPL proteins, prostate cancer, signal transduction, tumour necrosis factor receptor-associated factor 6, transforming growth factor beta
National Category
Cancer and Oncology
URN: urn:nbn:se:uu:diva-280903DOI: 10.18632/oncotarget.6346ISI: 000369950300023PubMedID: 26583432OAI: oai:DiVA.org:uu-280903DiVA: diva2:912324
Swedish Cancer Society, 100303Swedish Cancer Society, ALF-VLL-224051The Kempe Foundations, SMK. 1132Knut and Alice Wallenberg Foundation, 2012.0090
Available from: 2016-03-16 Created: 2016-03-16 Last updated: 2016-04-01Bibliographically approved

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Heldin, Carl-Henrik
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Ludwig Institute for Cancer Research
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