TGF-β promotes PI3K-AKT signaling and prostate cancer cell migration through the TRAF6-mediated ubiquitylation of p85α

• DOI: 10.1126/scisignal.aal4186
• Publication Date: 2017-10-05T20:05:21Z
• Authors: Anahita Hamidi; Jie Song; Noopur Thakur; Susumu Itoh; Anders Marcusson; Anders Bergh; Carl-Henrik Heldin; Maréne Landström
• Keywords: Male; Mice, Knockout; TNF Receptor-Associated Factor 6; 0301 basic medicine; Lysine; Receptor, Transforming Growth Factor-beta Type I; Prostatic Neoplasms; Apoptosis; Fibroblasts; Protein Serine-Threonine Kinases; Embryo, Mammalian; 3. Good health; Class Ia Phosphatidylinositol 3-Kinase; Mice; 03 medical and health sciences; Cell Movement; Animals; Humans; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptors, Transforming Growth Factor beta; Cells, Cultured; Signal Transduction

Transforming growth factor-β (TGF-β) is a pluripotent cytokine that regulates cell fate and plasticity in normal tissues tumors. The multifunctional cellular responses evoked by TGF-β are mediated the canonical SMAD pathway noncanonical pathways, including mitogen-activated protein kinase (MAPK) pathways phosphatidylinositol 3'-kinase (PI3K)-protein B (AKT) pathway. We found activated PI3K manner dependent on activity of E3 ubiquitin ligase tumor necrosis factor receptor-associated 6 (TRAF6). TRAF6 polyubiquitylated regulatory subunit p85α promoted formation complex between type I receptor (TβRI) p85α, which led to activation AKT. Lys63-linked polyubiquitylation Lys513 Lys519 iSH2 (inter-Src homology 2) domain was required for TGF-β-induced PI3K-AKT signaling motility prostate cancer cells macrophages. Unlike TRAF6-mediated AKT not TβRI. In situ proximity ligation assays revealed evident aggressive tissues. Thus, our data reveal molecular mechanism activates drive migration.