TRAF6

Official Full Name

TNF receptor associated factor 6

Organism

Homo sapiens

GeneID

7189

Background

The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins are associated with, and mediate signal transduction from, members of the TNF receptor superfamily. This protein has an amino terminal RING domain which is followed by four zinc-finger motifs, a central coiled-coil region and a highly conserved carboxyl terminal domain, known as the TRAF-C domain and mediates signaling from members of the TNF receptor superfamily as well as the Toll/IL-1 family. Signals from receptors such as CD40, TNFSF11/RANCE and IL-1 have been shown to be mediated by this protein. This protein also interacts with various protein kinases including IRAK1/IRAK, SRC and PKCzeta, which provides a link between distinct signaling pathways. This protein functions as a signal transducer in the NF-kappaB pathway that activates IkappaB kinase (IKK) in response to proinflammatory cytokines. The interaction of this protein with UBE2N/UBC13, and UBE2V1/UEV1A, which are ubiquitin conjugating enzymes catalyzing the formation of polyubiquitin chains, has been found to be required for IKK activation by this protein. This protein also interacts with the transforming growth factor (TGF) beta receptor complex and is required for Smad-independent activation of the JNK and p38 kinases. The protein encoded by this gene is a key molecule in antiviral innate and antigen-specific immune responses. [provided by RefSeq, Nov 2021]

Synonyms

RNF85; MGC:3310;

Cat.No.	Product Name	Price

Cat.No.	Product Name	Price

Cat.No.	Product Name	Price

Cat.No.	Product Name	Price

Detailed Information

Tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6), an E3 ubiquitin (Ub) ligase, is a signal transducer for the interleukin-1 (IL-1) receptor/Toll-like receptor (IL-1R/TLR) superfamily, including in response to cytokines, damage-associated molecular patterns, and pattern-associated molecular patterns. TRAF6 functions as an important signaling molecule to regulate a diverse array of physiological processes, including innate immunity, adaptive immunity, bone metabolism, and the development of skin, mammary glands, lymph nodes, and the central nervous system.

TRAF6-Related Pathways

Among the members of TRAF family, TRAF6 has unique properties, which can not only mediate tumor necrosis factor receptor (TNFR) family signaling, but also affect signaling downstream of an unrelated receptor family, the IL-1R/TLR superfamily. TRAF6 is also an important E3 ubiquitin ligase, and cooperates with the dimeric ubiquitin-conjugating enzyme Ubc13/Uev1A to promote the unique Lys-63-linked poly-ubiquitin chains, instead of the conventional Lys-48-linked poly-ubiquitin chains that target proteins for degradation. It also interacts with various protein kinases including SRC, IRAK1 and PKCzeta, which provides a link between distinct signaling pathways. Apart from regulating the activity of IKK/NF-κB signaling, TRAF6 also modifies other proteins or signaling. TRAF6 was found to mediate activation of AKT, p38 and JNK. Linares et al. showed that TRAF6 was involved in mTOR activation through K63 polyubiquitination. Wei et al. demonstrated that TRAF6 negatively regulates the JAK-STAT signaling. TRAF6 expression is increased in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients, and its overexpression leads to hematopoietic defects in mouse genetic models. Besides, deletion of miR-146a and TIFAB, negative regulators of TRAF6 expression and function, are commonly observed in MDS and AML.

TRAF6 and Cancer

Some studies have shown that TRAF6 may play a role in cancer. A recent study identifies TRAF6 as a commonly amplified oncogene bridging NF-B and RAS in lung cancer. Overexpression of TRAF6 in primary mouse marrow cells led to a myelodysplastic syndrome that develops into a fatal acute myeloid leukemia. A positive correlation between TRAF6 in tumor margin cells and the histological grade and the mode of tumor invasion was found in laryngeal carcinoma. TRAF6 mediates oncogenesis of marginal zone B cell lymphoma of mucosa-associated lymphoid tissue. It promotes proliferation and regulates apoptosis of osteosarcoma, glioma, esophageal cancer and lung adenocarcinoma cells. TRAF6 promoted the migration and metastasis of esophageal squamous cell carcinoma (ESCC) cells by modulating Ras signaling. Overexpression of TRAF6 can promote the migration of ESCC cells and immortalized esophageal epithelial cells, but knock down the expression of TRAF6 can inhibit the migration and metastasis of ESCC cells in vivo and in vitro. TRAF6 mechanically binds Ras with its N-terminal and activated Ras signaling. Therefore, TRAF6 played an important role in the metastasis of ESCC cells and may be a promising therapeutic target.

In addition, TRAF6 expression was higher and more consistent in human cancer cell lines. And TRAF6 protein levels were found higher in myelodysplastic syndrome patients. It has been reported that amplification of the TRAF6 locus was a somatic and frequent event in a variety of human cancer types. TRAF6 is overexpressed in primary and metastatic melanoma tumors. Knockdown of TRAF6 significantly blocked melanoma cell invasion and metastasis in vivo and in vitro. Moreover, TRAF6 can directly interact with and ubiquitinate BSG resulting in MMP9 induction, which serves as a mechanism for melanoma invasion and metastasis. In addition, the expression of TRAF6 is upregulated in colon cancer, which is associated with tumor grades. TRAF6 promotes the proliferation of colon cancer cells through cyclin D1. These results indicate that TRAF6 plays an important role in the development of colon cancer. And it may become a potential target for colon cancer chemotherapy.

References:

Sun H, et al. TRAF6 inhibition rescues dexamethasone-induced muscle atrophy. International journal of molecular sciences, 2014, 15(6): 11126-11141.
Hindi S M, Kumar A. TRAF6 regulates satellite stem cell self-renewal and function during regenerative myogenesis. The Journal of clinical investigation, 2016, 126(1): 151-168.
Fang J, et al. TRAF6 mediates basal activation of NF-κB necessary for hematopoietic stem cell homeostasis. Cell reports, 2018, 22(5): 1250-1262.
Luo Z, et al. TRAF6 regulates melanoma invasion and metastasis through ubiquitination of Basigin. Oncotarget, 2016, 7(6): 7179.
Sun H, et al. TRAF6 is upregulated in colon cancer and promotes proliferation of colon cancer cells. The international journal of biochemistry & cell biology, 2014, 53: 195-201.
Han Q, et al. TRAF6 promoted the metastasis of esophageal squamous cell carcinoma. Tumor Biology, 2014, 35(1): 715-721.

Quick Inquiry

Interested in learning more?

Contact us today for a free consultation with the scientific team and discover how Creative Biogene can be a valuable resource and partner for your organization.

Request a quote today!

Inquiry