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TRAF6 ubiquitinates TGFβ type I receptor to promote its cleavage and nuclear translocation in cancer

Author

Listed:
  • Yabing Mu

    (Rudbeck Laboratory, Genetics and Pathology
    Ludwig Institute for Cancer Research, Uppsala University)

  • Reshma Sundar

    (Rudbeck Laboratory, Genetics and Pathology
    Medical Biosciences, Umeå University)

  • Noopur Thakur

    (Rudbeck Laboratory, Genetics and Pathology
    Ludwig Institute for Cancer Research, Uppsala University)

  • Maria Ekman

    (Ludwig Institute for Cancer Research, Uppsala University)

  • Shyam Kumar Gudey

    (Rudbeck Laboratory, Genetics and Pathology
    Ludwig Institute for Cancer Research, Uppsala University)

  • Mariya Yakymovych

    (Ludwig Institute for Cancer Research, Uppsala University)

  • Annika Hermansson

    (Rudbeck Laboratory, Genetics and Pathology)

  • Helen Dimitriou

    (Rudbeck Laboratory, Genetics and Pathology
    Present addresses: Department of Pediatric Hemtology- Oncology, University of Crete, Medical School, Greece (H.D.); University College Dublin, School of Medicine and Medical Science, Conway Institute, Belfield, Dublin, Ireland (M.T.B.-A. and J.E.).)

  • Maria Teresa Bengoechea-Alonso

    (Ludwig Institute for Cancer Research, Uppsala University
    Present addresses: Department of Pediatric Hemtology- Oncology, University of Crete, Medical School, Greece (H.D.); University College Dublin, School of Medicine and Medical Science, Conway Institute, Belfield, Dublin, Ireland (M.T.B.-A. and J.E.).)

  • Johan Ericsson

    (Ludwig Institute for Cancer Research, Uppsala University
    Present addresses: Department of Pediatric Hemtology- Oncology, University of Crete, Medical School, Greece (H.D.); University College Dublin, School of Medicine and Medical Science, Conway Institute, Belfield, Dublin, Ireland (M.T.B.-A. and J.E.).)

  • Carl-Henrik Heldin

    (Ludwig Institute for Cancer Research, Uppsala University)

  • Marene Landström

    (Rudbeck Laboratory, Genetics and Pathology
    Ludwig Institute for Cancer Research, Uppsala University
    Medical Biosciences, Umeå University)

Abstract

Transforming growth factor β (TGFβ) is a pluripotent cytokine promoting epithelial cell plasticity during morphogenesis and tumour progression. TGFβ binding to type II and type I serine/threonine kinase receptors (TβRII and TβRI) causes activation of different intracellular signaling pathways. TβRI is associated with the ubiquitin ligase tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6). Here we show that TGFβ, via TRAF6, causes Lys63-linked polyubiquitination of TβRI, promoting cleavage of TβRI by TNF-alpha converting enzyme (TACE), in a PKCζ-dependent manner. The liberated intracellular domain (ICD) of TβRI associates with the transcriptional regulator p300 to activate genes involved in tumour cell invasiveness, such as Snail and MMP2. Moreover, TGFβ-induced invasion of cancer cells is TACE- and PKCζ- dependent and the TβRI ICD is localized in the nuclei of different kinds of tumour cells in tissue sections. Thus, our data reveal a specific role for TβRI in TGFβ mediated tumour invasion.

Suggested Citation

  • Yabing Mu & Reshma Sundar & Noopur Thakur & Maria Ekman & Shyam Kumar Gudey & Mariya Yakymovych & Annika Hermansson & Helen Dimitriou & Maria Teresa Bengoechea-Alonso & Johan Ericsson & Carl-Henrik He, 2011. "TRAF6 ubiquitinates TGFβ type I receptor to promote its cleavage and nuclear translocation in cancer," Nature Communications, Nature, vol. 2(1), pages 1-11, September.
    • Handle: RePEc:nat:natcom:v:2:y:2011:i:1:d:10.1038_ncomms1332
    DOI: 10.1038/ncomms1332
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