title: APPL proteins promote TGFβ-induced nuclear transport of the TGFβ type I receptor intracellular domain.
abstract: 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.
authors.affiliation: Medical Biosciences, Umeå University, Umeå, Sweden.
authors.forename: Jie
authors.initials: J
authors.lastname: Song
authors.affiliation: Medical Biosciences, Umeå University, Umeå, Sweden.
authors.forename: Yabing
authors.initials: Y
authors.lastname: Mu
authors.affiliation: Implant Center, Stomatological Hospital, Jilin University, Changchun, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Li
authors.affiliation: Medical Biosciences, Umeå University, Umeå, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Bergh
authors.affiliation: International Institute of Molecular and Cell Biology, Laboratory of Cell Biology, Warsaw, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Miaczynska
authors.affiliation: Ludwig Institute for Cancer Research Ltd, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Carl-Henrik
authors.initials: CH
authors.lastname: Heldin
authors.affiliation: Medical Biosciences, Umeå University, Umeå, Sweden.
authors.forename: Marene
authors.initials: M
authors.lastname: Landström
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D008297:Male; D018613:Microscopy, Confocal; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: C464801:APPL1 protein, human; C528555:APPL2 protein, human; D048868:Adaptor Proteins, Signal Transducing; D018125:Receptors, Transforming Growth Factor beta; D048029:TNF Receptor-Associated Factor 6; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I
keywords: APPL proteins; prostate cancer; signal transduction; transforming growth factor β; tumour necrosis factor receptor-associated factor 6