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

Singh, Ramesh; Karri, Dileep; Shen, Hong; Shao, Juntao; Dasgupta, Subhamoy; Huang, Shixia; Edwards, Dean P.; Ittmann, Michael; O’Malley, Bert W.; Yi, Ping

doi:10.1172/jci96060

Cited by 64 publications

(73 citation statements)

References 71 publications

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“…Studies have confirmed that ubiquitination is an important posttranslational modification [19]. In clinical researches, ubiquitinated dysfunction could upregulate many oncogenic proteins that result in tumor formation [20][21][22].…”

Section: Discussionmentioning

confidence: 95%

CHIP-mediated ubiquitination of Galectin-1 predicts colorectal cancer prognosis

et al. 2020

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CHIP and Galectin-1 are associated with the development of metastasis in cancer. However, the precise roles of CHIP or Gal1 in colorectal cancer are uncertain. Here, our study explored the relationship and clinical significance of CHIP or Gal1 in CRC. CHIP or Gal1 expression was significantly decreased or up-regulated in CRC compared with adjacent noncancerous tissues by immunohistochemistry on a CRC tissue microarray, respectively. Low CHIP or high Gal1 expression significantly correlated with clinicopathological characteristics in patients, as well as with shorter overall survival. Multivariate Cox regression analysis revealed that CHIP or Gal1 expression was an independent prognostic factor for CRC patients. Moreover, CHIP associated with Gal1 has a synergistic effect on the prediction of CRC prognosis. In vitro and vivo, high CHIP or low Gal1 expression inhibit CRC growth or metastasis. Our results found that CHIP could degradate Gal1 by ubiquitination. In summary, CHIP could inhibit CRC growth or metastasis through promoting Gal1 ubiquitination and degradation by proteasome. CHIP and Gal1 expressions are novel candidate prognostic markers in CRC. A combined effect of CHIP and Gal1 as efficient prognostic indicators was found for the first time.

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Section: Discussionmentioning

confidence: 95%

CHIP-mediated ubiquitination of Galectin-1 predicts colorectal cancer prognosis

et al. 2020

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“…Accumulating studies have demonstrated that TRAF4 interacts with several molecules to function in certain circumstances [25,26]. Thus, we speculated that TRAF4 may interact with some classical osteogenesis-related molecules to modulate the osteogenic differentiation of MSCs.…”

Section: Traf4 Diminishes the Expression Of Smurf2 To Modulate Osteogmentioning

confidence: 91%

TRAF4 positively regulates the osteogenic differentiation of mesenchymal stem cells by acting as an E3 ubiquitin ligase to degrade Smurf2

Wang

Xie

et al. 2019

Cell Death Differ

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TNF receptor-associated factor 4 (TRAF4), a member of the TRAF family, plays an important role in the embryogenesis and development of the bone system. Mesenchymal stem cells (MSCs), which are the primary origin of osteoblasts in vivo, are key cells in bone development; however, whether TRAF4 modulates the osteogenic capacity of MSCs has never been explored. In this study, we demonstrated that TRAF4 positively regulates the osteogenic process of MSCs both in vitro and in vivo. In addition, we further demonstrated that TRAF4 modulates the osteogenic process of MSCs by acting as an E3 ubiquitin ligase to mediate the K48-linked ubiquitination of Smurf2 at the K119 site and cause degradation. Furthermore, TRAF4 was abnormally decreased in bone sections of ovariectomized rat and osteoporosis patients. Taken together, our findings suggest that TRAF4 positively regulates the osteogenic differentiation of MSCs by acting as an E3 ubiquitin ligase to degrade Smurf2. These results emphasize the critical role of TRAF4 in bone formation and could not only improve the clinical use of MSCs in tissue engineering but also clarify the pathogenesis of bone metabolism disorders.

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“…Available human evidence indicates that gene amplification is the most common TRAF4 genetic alteration in cancers and that TRAF4 expression is ubiquitously elevated in many human cancers ( 196 – 204 ). This suggests that TRAF4 overexpression may play causal roles in cancer initiation, progression and metastasis.…”

Section: Traf4mentioning

confidence: 99%

“…In addition to the established IL-17A-TRAF4-ERK5 axis, a variety of potential TRAF4 -dependent oncogenic pathways have been suggested by studies of patient samples, cultured human cancer cells or their xenografts in immunodeficient mice. These include: (1) TRAF4-Akt/NF-κB-Glut1/HK2/RSK4/Slug in the proliferation and metastasis of lung and breast cancer cells as well as the migration and epithelial-mesenchymal transition (EMT) of hepatocellular carcinoma cells (HCC) ( 199 , 203 , 206 ); (2) TGFβ-TβRI-TRAF4-Smurf1/Smurf2/USP15-SMAD2/TAK1-N-cadherin/Fibronectin/Vimentin/SMA in the migration, EMT, and metastasis of breast cancer cells ( 200 , 207 ); (3) SRC3-TRAF4-mediated inhibition of the USP7-p53 interaction, leading to the loss of p53 deubiquitination/stabilization and thus the resistance to cytotoxic drugs and stress in breast cancer ( 208 ); (4) NGF-TrkA-TRAF4-Akt/p38-IL-6/Integrins/COX2 in the metastasis of prostate cancer cells ( 204 ); (5) TNFα-TRAF4/TRAF2-NF-κB1 in the survival and proliferation of breast cancer cells ( 209 ); (6) TRAF4-mediated up-regulation and nuclear translocation of β-catenin in the Wnt/β-catenin-cyclin D1/c-myc/Bcl-2/MMPs pathway that promote the growth and migration of OSCC and breast cancer cells ( 210 , 211 ); (7) TRAF4-mTOR-p70S6K-S6 in the proliferation of breast cancer cells ( 212 ); and (8) the TRAF4-phosphoinositide (PIP) interaction at tight junctions that favors breast cancer cell migration ( 213 ). It would be interesting to verify these TRAF4-dependent oncogenic pathways using in vivo models.…”

Section: Traf4mentioning

confidence: 99%

Genetic Alterations of TRAF Proteins in Human Cancers

et al. 2018

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The tumor necrosis factor receptor (TNF-R)-associated factor (TRAF) family of cytoplasmic adaptor proteins regulate the signal transduction pathways of a variety of receptors, including the TNF-R superfamily, Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), and cytokine receptors. TRAF-dependent signaling pathways participate in a diverse array of important cellular processes, including the survival, proliferation, differentiation, and activation of different cell types. Many of these TRAF-dependent signaling pathways have been implicated in cancer pathogenesis. Here we analyze the current evidence of genetic alterations of TRAF molecules available from The Cancer Genome Atlas (TCGA) and the Catalog of Somatic Mutations in Cancer (COSMIC) as well as the published literature, including copy number variations and mutation landscape of TRAFs in various human cancers. Such analyses reveal that both gain- and loss-of-function genetic alterations of different TRAF proteins are commonly present in a number of human cancers. These include pancreatic cancer, meningioma, breast cancer, prostate cancer, lung cancer, liver cancer, head and neck cancer, stomach cancer, colon cancer, bladder cancer, uterine cancer, melanoma, sarcoma, and B cell malignancies, among others. Furthermore, we summarize the key in vivo and in vitro evidence that demonstrates the causal roles of genetic alterations of TRAF proteins in tumorigenesis within different cell types and organs. Taken together, the information presented in this review provides a rationale for the development of therapeutic strategies to manipulate TRAF proteins or TRAF-dependent signaling pathways in different human cancers by precision medicine.

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

Cited by 64 publications

References 71 publications

CHIP-mediated ubiquitination of Galectin-1 predicts colorectal cancer prognosis

CHIP-mediated ubiquitination of Galectin-1 predicts colorectal cancer prognosis

TRAF4 positively regulates the osteogenic differentiation of mesenchymal stem cells by acting as an E3 ubiquitin ligase to degrade Smurf2

Genetic Alterations of TRAF Proteins in Human Cancers

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