期刊
CELL COMMUNICATION AND SIGNALING
卷 15, 期 -, 页码 -出版社
BIOMED CENTRAL LTD
DOI: 10.1186/s12964-017-0174-1
关键词
Death receptor 5; Invasion; S1P; Caspase-8; TRAF2; Polyubiquitination
类别
资金
- NIH/NCI SPORE P50 grant [CA128613]
- NIH/NCI cancer center P30 grant [CA138292]
- Emory Winship Cancer Institute Robbins Scholar award
- Emory Winship Cancer Institute Halpern Research Scholar award
Background: Death 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. Results: DR5 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. Conclusions: Both 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.
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