The ubiquitin-ligase TRAF6 and TGFβ type I receptor form a complex with Aurora kinase B contributing to mitotic progression and cytokinesis in cancer cells

BACKGROUND: Transforming growth factor β (TGFβ) is overexpressed in several advanced cancer types and promotes tumor progression. We have reported that the intracellular domain (ICD) of TGFβ receptor (TβR) I is cleaved by proteolytic enzymes in cancer cells, and then translocated to the nucleus in a manner dependent on the endosomal adaptor proteins APPL1/2, driving an invasiveness program. How cancer cells evade TGFβ-induced growth inhibition is unclear. METHODS: We performed microarray analysis to search for genes regulated by APPL1/2 proteins in castration-resistant prostate cancer (CRPC) cells. We investigated the role of TβRI and TRAF6 in mitosis in cancer cell lines cultured in 10% FBS in the absence of exogenous TGFβ. The molecular mechanism of the ubiquitination of AURKB by TRAF6 in mitosis and the formation of AURKB–TβRI complex in cancer cell lines and tissue microarrays was also studied. FINDINGS: During mitosis and cytokinesis, AURKB–TβRI complexes formed in midbodies in CRPC and KELLY neuroblastoma cells. TRAF6 induced polyubiquitination of AURKB on K85 and K87, protruding on the surface of AURKB to facilitate its activation. AURKB–TβRI complexes in patient's tumor tissue sections correlated with the malignancy of prostate cancer. INTERPRETATION: The AURKB–TβRI complex may become a prognostic biomarker for patients with risk of developing aggressive PC. FUNDING: Swedish Medical Research Council (2019-01598, ML; 2015-02757 and 2020-01291, CHH), the Swedish Cancer Society (20 0964, ML), a regional agreement between Umeå University and Region Västerbotten (ALF; RV-939377, -967041, -970057, ML). The European Research Council (787472, CHH). KAW 2019.0345, and the Kempe Foundation SMK-1866; ML. National Microscopy Infrastructure (NMI VR-RFI 2016-00968).