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

被引：176

作者：

Hamidi, Anahita ^{[1
,2
]}

Song, Jie ^{[3
]}

Thakur, Noopur ^{[1
,2
]}

Itoh, Susumu ^{[4
]}

Marcusson, Anders ^{[1
,2
]}

Bergh, Anders ^{[3
]}

Heldin, Carl-Henrik ^{[1
,2
]}

Landstrom, Marene ^{[1
,2
,3
]}

机构：

[1] Uppsala Univ, Ludwig Inst Canc Res, SE-75124 Uppsala, Sweden

[2] Uppsala Univ, Sci Life Lab, SE-75124 Uppsala, Sweden

[3] Umea Univ, Dept Med Biosci, Unit Pathol, SE-90185 Umea, Sweden

[4] Showa Pharmaceut Univ, Biochem Lab, Tokyo 1948543, Japan

来源：

SCIENCE SIGNALING | 2017年 / 10卷 / 486期

基金：

英国医学研究理事会; 瑞典研究理事会;

关键词：

EPITHELIAL-MESENCHYMAL TRANSITION; REGULATES AKT UBIQUITINATION; I RECEPTOR; KAPPA-B; CATALYTIC SUBUNIT; INDUCED INVASION; ACTIVATION; TRAF6; PROTEINS; COMPLEX;

D O I：

10.1126/scisignal.aal4186

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Transforming growth factor-b (TGF-beta) is a pluripotent cytokine that regulates cell fate and plasticity in normal tissues and tumors. The multifunctional cellular responses evoked by TGF-beta 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-b 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 p85 alpha and promoted the formation of a complex between the TGF-beta type I receptor (T beta RI) and p85 alpha, which led to the activation of PI3K and AKT. Lys(63)-linked polyubiquitylation of p85 alpha on Lys(513) and Lys(519) in the iSH2 (inter-Src homology 2) domain was required for TGF-beta-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 TbRI. In situ proximity ligation assays revealed that polyubiquitylation of p85a was evident in aggressive prostate cancer tissues. Thus, our data reveal a molecular mechanism by which TGF-b activates the PI3K-AKT pathway to drive cell migration.

引用

页数：15