The phosphoinositide-binding protein TRAF4 modulates tight junction stability and migration of cancer cells

Rousseau, Adrien; Wilhelm, Léa P; Tomasetto, Catherine; Alpy, Fabien

doi:10.4161/21688370.2014.975597

Cited by 12 publications

(8 citation statements)

References 33 publications

(59 reference statements)

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“…We also found that TRAF4 protein levels were significantly higher in 7 of 10 human prostate tumors compared with matched benign prostate tissues ( Figure 1B). Since TRAF4 has been reported to be associated with cell migration and cancer metastasis (9,15,18,33,34), we also analyzed its expression in several publicly available prostate cancer datasets containing a substantial number of metastatic cancers (35)(36)(37)(38)(39). Consistent with our analysis of tumors ( Figure 1, A and B), TRAF4 expression was significantly elevated in prostate tumors compared with adjoining prostate tissues (Figure 1, C-F).…”

Section: Resultssupporting

confidence: 69%

TRAF4-mediated ubiquitination of NGF receptor TrkA regulates prostate cancer metastasis

Singh¹,

Karri²,

Shen³

et al. 2018

Journal of Clinical Investigation

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Receptor tyrosine kinases (RTKs) are important drivers of cancers. In addition to genomic alterations, aberrant activation of WT RTKs plays an important role in driving cancer progression. However, the mechanisms underlying how RTKs drive prostate cancer remain incompletely characterized. Here we show that non-proteolytic ubiquitination of RTK regulates its kinase activity and contributes to RTK-mediated prostate cancer metastasis. TRAF4, an E3 ubiquitin ligase, is highly expressed in metastatic prostate cancer. We demonstrated here that it is a key player in regulating RTK-mediated prostate cancer metastasis. We further identified TrkA, a neurotrophin RTK, as a TRAF4-targeted ubiquitination substrate that promotes cancer cell invasion and found that inhibition of TrkA activity abolished TRAF4-dependent cell invasion. TRAF4 promoted K27- and K29-linked ubiquitination at the TrkA kinase domain and increased its kinase activity. Mutation of TRAF4-targeted ubiquitination sites abolished TrkA tyrosine autophosphorylation and its interaction with downstream proteins. TRAF4 knockdown also suppressed nerve growth factor (NGF) stimulated TrkA downstream p38 MAPK activation and invasion-associated gene expression. Furthermore, elevated TRAF4 levels significantly correlated with increased NGF-stimulated invasion-associated gene expression in prostate cancer patients, indicating that this signaling axis is significantly activated during oncogenesis. Our results revealed a posttranslational modification mechanism contributing to aberrant non-mutated RTK activation in cancer cells.

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Section: Resultssupporting

confidence: 69%

TRAF4-mediated ubiquitination of NGF receptor TrkA regulates prostate cancer metastasis

Singh¹,

Karri²,

Shen³

et al. 2018

Journal of Clinical Investigation

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“…TRAF4 has a 'TRAF' domain at its C-terminal region, which mediates trimer formation with other TRAF4 molecules; trimers are capable of binding phosphatidylinositol trisphosphate (PIP3) molecules which tethers them to the plasma membrane [16]. This feature allows TRAF4 molecules to localize to the plasma membrane and regulate tight junction stability [17,18]. Since, Serine334 is located on the TRAF domain, we hypothesized that phosphorylation of this residue would cause mis-localization of TRAF4.…”

Section: Traf4 Is Epigenetically Repressed and Gets Phosphorylated Atmentioning

confidence: 99%

TRAF4 inhibits bladder cancer progression by promoting BMP/SMAD signalling pathway

Iyengar

Marvin

Tan

et al. 2020

Preprint

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Bladder cancer is one of the most prevalent cancer types in the world, frequently exhibiting invasion and metastasis and therefore associated with poor prognosis. It is a progressive disease with high recurrence rates even after surgery, which calls for the urgent need for early intervention and diagnosis. The E3 ubiquitin ligase TNF Receptor Associated Factor 4 (TRAF4) has been largely implicated as a tumour-promoting element in a wide range of cancers. Over-expression and amplification of this gene product has been a common observation in breast and other metastatic tumours. In contrast, we observed that expression of TRAF4 negatively correlated with overall patient survival. Moreover, its expression was repressed at epigenetic levels in aggressive bladder cancer cells. We also describe an ERK kinase phosphorylation site on TRAF4 that inhibits its stability and localization to plasma membrane in such cells. Furthermore, knockdown of TRAF4 in epithelial bladder cancer cell lines leads to gain of mesenchymal genes and a loss of epithelial integrity. Reciprocally, stable over-expression of TRAF4 in mesenchymal cells leads to decreased migratory and invasive properties. Transcriptomic analysis upon TRAF4 mis-expression in bladder cancer cell lines revealed that higher TRAF4 expression enhanced BMP/SMAD and dampened NF-κB signalling pathways. Importantly, this notion was confirmed in bladder cancer patient material. Mechanistically, we showed that TRAF4 targets the E3 ubiquitin ligase SMURF1, a negative regulator of BMP/SMAD signalling, for proteasomal degradation in bladder cancer cells. We show that genetic and pharmacological inhibition of SMURF1 or its function inhibited migration of aggressive (mesenchymal) bladder cancer cells.

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“…Moreover, although it has been confirmed that TRAF4 is widely expressed in adult tissues, its subcellular localization has been controversial for years (Shen et al, 2013;Yi et al, 2013). The mainstream views hold that it is broadly located in the cell membrane, cytoplasm, and nucleus (Rousseau et al, 2014;Ren et al, 2015). Perhaps due to the particularity of its structure and expression, TRAF4 plays an important role in developmental steps, such as tracheal ring formation, neural tube closure, and axial skeleton formation (Kim E. et al, 2017).…”

Section: Traf4mentioning

confidence: 99%

“…Firstly, TRAF4 is an ancestral member, due to the fact that other TRAFs members (except TRAF6) have evolved to a certain extent ( Cai et al, 2017 ). Secondly, TRAF4 is the only member that has three cysteine-rich motifs associated with TRAF and RING domains, followed by seven zinc fingers ( Rousseau et al, 2014 ; Yang et al, 2015 ). In addition, TRAF4 has the canonical NLS sequence, similar to TRAF3 ( Mambetsariev et al, 2016 ; Das et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Roles of TRAFs in Ischemia-Reperfusion Injury

Wei

Lin

Zhong

et al. 2020

Front. Cell Dev. Biol.

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Tumor necrosis factor receptor-associated factor (TRAF) proteins are a family of signaling molecules that function downstream of multiple receptor signaling pathways, and they play a pivotal role in the regulation of intracellular biological progresses. These TRAFdependent signaling pathways and physiological functions have been involved in the occurrence and progression of ischemia-reperfusion injury (IRI), which is a common pathophysiological process that occurs in a wide variety of clinical events, including ischemic shock, organ transplantation, and thrombolytic therapy, resulting in a poor prognosis and high mortality. IRI occurs in multiple organs, including liver, kidney, heart, lung, brain, intestine, and retina. In recent years, mounting compelling evidence has confirmed that the genetic alterations of TRAFs can cause subversive phenotype changes during IRI of those organs. In this review, based on current knowledge, we summarized and analyzed the regulatory effect of TRAFs on the IRI of various organs, providing clear direction and a firm theoretical basis for the development of treatment strategies to manipulate TRAF proteins or TRAF-dependent signaling pathways in IRI-related diseases.

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The phosphoinositide-binding protein TRAF4 modulates tight junction stability and migration of cancer cells

Cited by 12 publications

References 33 publications

TRAF4-mediated ubiquitination of NGF receptor TrkA regulates prostate cancer metastasis

TRAF4-mediated ubiquitination of NGF receptor TrkA regulates prostate cancer metastasis

TRAF4 inhibits bladder cancer progression by promoting BMP/SMAD signalling pathway

Roles of TRAFs in Ischemia-Reperfusion Injury

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