APPL proteins promote TGFβ-induced nuclear transport of the TGFβ type I receptor intracellular domain
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Jie Song1,*, Yabing Mu1,*, Chunyan Li2, Anders Bergh1, Marta Miaczynska3, Carl-Henrik Heldin4, Marene Landström1
1Medical Biosciences, Umeå University, Umeå, Sweden
2Implant Center, Stomatological Hospital, Jilin University, Changchun, China
3International Institute of Molecular and Cell Biology, Laboratory of Cell Biology, Warsaw, Poland
4Ludwig Institute for Cancer Research Ltd, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
*These authors contributed equally to this work
Marene Landström, e-mail: [email protected]
Keywords: APPL proteins, prostate cancer, signal transduction, tumour necrosis factor receptor-associated factor 6, transforming growth factor β
Received: October 07, 2015 Accepted: November 09, 2015 Published: November 18, 2015
The multifunctional cytokine transforming growth factor-β (TGFβ) 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 TGFβ type I receptor (TβRI) 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 TβRI in cancer cells. Subsequently, the intracellular domain (ICD) of TβRI 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 TGFβ-induced nuclear translocation of TβRI-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 TβRI in a TRAF6-dependent manner. Our results suggest that the APPL–TβRI complex promotes prostate tumour progression, and may serve as a prognostic marker.
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