DR5 suppression induces sphingosine-1-phosphate-dependent TRAF2 polyubiquitination, leading to activation of JNK/AP-1 and promotion of cancer cell invasion

Cell Communication and Signaling

Research

Shi-Yong Sun¹  Ping Yue¹  You-Take Oh¹ 

[1] Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, 1365-C Clifton Road, Clinical Building C3088, 30322, Atlanta, GA, USA;

关键词: Death receptor 5;    Invasion;    S1P;    Caspase-8;    TRAF2;    Polyubiquitination;   

DOI  :  10.1186/s12964-017-0174-1

 received in 2017-02-23, accepted in 2017-05-02,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundDeath receptor (DR5), a well-characterized death domain-containing cell surface pro-apoptotic protein, has been suggested to suppress cancer cell invasion and metastasis. However, the underlying mechanisms have not been fully elucidated. Our recent work demonstrates that DR5 suppression promotes cancer cell invasion and metastasis through caspase-8/TRAF2-mediated activation of ERK and JNK signaling and MMP1 elevation. The current study aimed at addressing the mechanism through which TRAF2 is activated in a caspase-8 dependent manner.ResultsDR5 knockdown increased TRAF2 polyubiquitination, a critical event for TRAF2-mediated JNK/AP-1 activation. Suppression of sphingosine-1-phosphate (S1P) generation or depletion of casapse-8 inhibited not only enhancement of cell invasion, but also elevation and polyubiquitination of TRAF2, activation of JNK/AP-1 activation and increased expression of MMP1 induced by DR5 knockdown.ConclusionsBoth S1P and caspase-8 are critical for TRAF2 stabilization, polyubiquitination, subsequent activation of JNK/AP1 signaling and MMP1 expression and final promotion of cell invasion.

【 授权许可】

CC BY   
© The Author(s). 2017