title: TRIP6 antagonizes the recruitment of A20 and CYLD to TRAF6 to promote the LPA2 receptor-mediated TRAF6 activation.
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.
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Fang-Tsyr
authors.initials: FT
authors.lastname: Lin
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Vivian Y
authors.initials: VY
authors.lastname: Lin
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, Baylor College of Medicine, Houston, TX, USA; Department of Cell Biology, University of Alabama at Birmingham, Alabama, AL, USA.
authors.forename: Victor Tg
authors.initials: VT
authors.lastname: Lin
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Weei-Chin
authors.initials: WC
authors.lastname: Lin
keywords: A20; CYLD; JNK; LPA; NF-κB; TRAF6; TRIP6