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Deregulation of the PI3K/AKT pathway has been reported in many types of cancer, including prostate cancer. As AKT regulates survival, metabolism, migration and therapy resistance in cancer cells, aberrant, high activity of AKT is involved in poor prognosis in cancer patients [1]. Transforming growth factor-β (TGFβ) family members are important for regulation of embryogenesis and tissue homeostasis, and high levels of TGFβ is correlated to cancer progression due to its potent regulatory effects on cells trans-differentiation, proliferation, migration and invasion of cancer cells [2]. Some of these effects are believed to occur due to that TGFβ promotes non-canonical Smad-signaling pathways, leading to activation of the PI3K AKT pathway, although the precise molecular mechanisms behind this event have not been revealed [2]. Ubiquitination, a dynamic post-translational modification, is one of the key mechanisms to regulate cellular processes via a single ubiquitin or ubiquitin chains covalently attached to an acceptor lysine of the target protein. Lys48-linked polyubiquitination usually mediates proteasomal degradation of target proteins, whereas Lys63-linked polyubiquitination performs various non-degradative regulatory roles, including endocytosis, DNA damage tolerance and signal transduction [3]. It has been reported that upon IGF-1 stimulation, AKT is ubiquitinated by E3 ligase TRAF6, leading to the membrane localization and phosphorylation of AKT [4]. Our recent data shows that TGFβ stimulation, via TRAF6, caused the Lys63-linked polyubiquitination of p85α, which leads to activation of the PI3K pathway followed by membrane recruitment of AKT and thereby its activation (Figure 1) [5]. We demonstrated that AKT interacts with TRAF6 upon TGFβ simulation. TGFβ induces polyubiquitination of AKT in a TRAF6 dependent manner and the polyubiquitination is correlated with the activation of AKT. The phosphorylation of AKT by TGFβ is not affected by TβRI kinase but in contrast, is dependent on PI3K activity. Moreover, p85α interacts with TβRI via its SH2 domains in a TRAF6-dependent manner. Upon TGFβ simulation, TRAF6, TβRI, phosphorylated AKT and p85α colocalize in cell membrane ruffles formed in migratory cells. TRAF6 induces polyubiquitination of p85α upon TGFβ simulation, which is independent of TβRI and TβRII kinase activity. We could also identify Lys513 and/or Lys519 in the iSH2 domain as the acceptor of polyubiquitination in p85 by mass spectrometry analysis. Polyubiquitination of p85α possibly results in a conformational change, thereby releasing the inhibitory contacts of SH2 domains of p85α from p110. Interestingly, by measuring the concentration of PIP3, we found that TRAF6 and p85α are important for the TGFβ-induced activation of PI3K [5]. We further demonstrated that the PI3K/AKT pathway and TRAF6 are important in TGFβ-induced cell migration. The treatment of the inhibitor of PI3K: wortmannin and LY294002 significantly decreases the migration of prostate cancer cells. The prostate cancer cells expressing double mutant K513R/K519R show reduced migration compared to wild-type Flag-p85α transfected cells, indicating that polyubiquitination of p85α is involved in the cell migration. Finally and importantly, by in situ proximity ligation, we found that Lys63-linked polyubiquitination of p85α is correlated with higher Gleason score, which indicates the aggressiveness and poor prognosis of prostate cancer, suggesting that Editorial

TGFβ activates PI3K-AKT signaling via TRAF6