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

Abstract

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

Retracted: Silencing of COL1A2, COL6A3, and THBS2 inhibits gastric cancer cell proliferation, migration, and invasion while promoting apoptosis through the PI3k‐Akt signaling pathway

“…Hamidi A also suggests that TGF‐b nay activate the PI3K signaling pathway, promote the migration of tumor cells. The correlation between TGF‐b and the PI3K signaling pathway was observed by former studies . Apart from that, Boguslawska et al demonstrate that TGF‐b, COL1A1, and THBS2 expression in gastric cancer cells are related to the survival time of gastric cancer patients, which suggests that COL1A1 and THBS2 may influence the activation of the PI3K signaling pathway by upregulating the TGF‐b.…”

Intracellular trafficking of transforming growth factor β receptors

“…As TGFβ activates Akt and induces the expression of CIN85 [49,50,86], these data suggest that recycling of TGFβ receptors can be regulated via a positive feedback loop, where TGFβ stimulation promotes the transport of the TGFβ receptors to the cell surface.…”

“…2). It has been also shown that Smad7 is required for the TGFβ-induced activation of the phosphatidylinositol 3′-kinase (PI3K)-protein kinase B (Akt) pathway [49,50]. It is not known, however, whether receptor signaling complexes containing Smad7 are located in caveolae in these cases.…”

A functional variant in TNXB promoter associates with the risk of esophageal squamous‐cell carcinoma

“…Men et al 25 demonstrated that TNXB mapped in pathways of focal adhesion, ECM receptor interaction, and calcium signaling pathway. Sanchez‐Antolín et al 37 previously reported that TNXB affected the activation of the TGF‐β signaling, and TGF‐β could interact with the PI3K‐Akt signaling, potentially 38 . Since the exact role or mechanism of TNXB in ESCC remained largely undiscovered, here, we conducted co‐expression and gene set enrichment analysis using mRNA expression data in ESCC.…”