Abstract
The elevated lysophosphatidic acid signaling has been causally linked to cancer-associated inflammation and tumorigenesis through upregulation of nuclear factor-κB signaling. However, how this signaling event is regulated has not yet been fully understood. Here we demonstrate that TRIP6, an LPA2 receptor-interacting adaptor protein, functions as a positive regulator of nuclear factor-κB and JNK signaling through direct binding to and activation of the E3 ligase TRAF6. Upon lysophosphatidic acid stimulation, TRIP6 recruits TRAF6 to the LPA2 receptor and promotes lysophosphatidic acid-induced JNK and nuclear factor-κB activation in a TRAF6-dependent manner. TRIP6 antagonizes the recruitment of deubiquitinases A20 and CYLD to TRAF6, thus sustaining the E3 ligase activity of TRAF6 and augmenting lysophosphatidic acid-activated nuclear factor-κB signaling. In contrast, depletion of TRIP6 by TRIP6-specific shRNA or Cas9/sgRNA greatly enhances the association of TRAF6 with A20 and CYLD, and attenuates lysophosphatidic acid-induced muclear factor-κB and JNK/p38 activation in ovarian cancer cells. On the other hand, TRAF6 also regulates TRIP6 by facilitating its binding to nuclear factor-κB p65 and phosphorylation by c-Src. Together, TRIP6 cooperates with TRAF6 to regulate the LPA2 receptor signaling, which may ultimately contribute to chronic inflammation, apoptotic resistance and cell invasion.
Highlights
Lysophosphatidic acid (LPA) is a growth factor-like phospholipid that mediates cell proliferation, apoptotic resistance, angiogenesis and cancer invasion and metastasis via binding to the G protein-coupled LPA receptors [1]
TRIP6 has been shown to regulate the nuclear factor-κB (NF-κB) signaling by serving as a coactivator of NF-κB p65 in the nucleus [25], our previous data show that knockdown of TRIP6 increases the association of IκBα with NF-κB p65 in the cytosol and attenuates LPA-induced nuclear translocation of NF-κB p65 [21], suggesting that TRIP6 may function as a further upstream regulator of NF-κB signaling
We further demonstrate a unique role for TRIP6 in the regulation of LPA-stimulated activation of NF-κB and JNK-activator protein-1 (AP-1) signaling through the recruitment of TRAF6 to the LPA2 receptor
Summary
Lysophosphatidic acid (LPA) is a growth factor-like phospholipid that mediates cell proliferation, apoptotic resistance, angiogenesis and cancer invasion and metastasis via binding to the G protein-coupled LPA receptors [1]. TRAF6 can bind to the MAP3K family members, such as MEKK1, ASK1 or TAK1, to promote JNK and p38 MAP kinase signaling pathways [4,5,6], which in turn activates the downstream activator protein-1 (AP-1) transcriptional activity to regulate cell proliferation, differentiation and other cellular responses. By catalyzing K63-linked ubiquitination of AKT at its PH domain, TRAF6 has been shown to promote the membrane translocation and activation of AKT [7]. These findings suggest that TRAF6 functions to integrate multiple signaling pathways involved in inflammation, antiapoptosis and cell proliferation
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