Disease relevance of TRADD

• The oncogenic Epstein-Barr virus (EBV)-encoded latent infection membrane protein 1 (LMP1) mimics a constitutive active tumor necrosis factor (TNF) family receptor in its ability to recruit TNF receptor-associated factors (TRAFs) and TNF receptor-associated death domain protein (TRADD) in a ligand-independent manner [1].
• Mutation analysis of the apoptotic "death-receptors" and the adaptors TRADD and FADD/MORT-1 in osteosarcoma tumor samples and osteosarcoma cell lines [2].
• Hepatitis C virus core protein enhances FADD-mediated apoptosis and suppresses TRADD signaling of tumor necrosis factor receptor [3].
• Despite constitutive association with TRADD or RIP, LMP1 does not induce apoptosis in EBV-negative Burkitt lymphoma or human embryonic kidney 293 cells [4].
• TRADD could be immunodetected after p75(NTR) immunoprecipitation from MCF-7 breast cancer cells stimulated by nerve growth factor [5].

High impact information on TRADD

• They can be recruited to activated TNF receptors either by direct interactions with the receptors or indirectly via the adaptor protein TRADD [6].
• A novel mechanism of TRAF signaling revealed by structural and functional analyses of the TRADD-TRAF2 interaction [6].
• MORT1 and TRADD can also bind to each other [7].
• However, NF-kappa B activation by TRADD is not inhibited by crmA expression, demonstrating that the signaling pathways for TNF-induced cell death and NF-kappa B activation are distinct [8].
• Here we show that upon TNFalpha binding, TNFR1 translocates to cholesterol- and sphingolipid-enriched membrane microdomains, termed lipid rafts, where it associates with the Ser/Thr kinase RIP and the adaptor proteins TRADD and TRAF2, forming a signaling complex [9].

Biological context of TRADD

• The death domain of tumor necrosis factor (TNF) receptor-1 (TNFR1) triggers distinct signaling pathways leading to apoptosis and NF-kappa B activation through its interaction with the death domain protein TRADD [10].
• Here, we show that TRADD interacts strongly with RIP, another death domain protein that was shown previously to associate with Fas antigen [10].
• A combination of NMR, BIAcore, and mutagenesis experiments was used to help identify the site of interaction of N-TRADD with C-TRAF2, providing a framework for future attempts to selectively inhibit the TNF signaling pathways [11].
• Phorbol 12-myristate 13-acetate protects against tumor necrosis factor (TNF)-induced necrotic cell death by modulating the recruitment of TNF receptor 1-associated death domain and receptor-interacting protein into the TNF receptor 1 signaling complex: Implication for the regulatory role of protein kinase C [12].
• Consequently, the molecular function of TRADD in LMP1 signaling differs from its role in TNFR1 signal transduction [13].

Anatomical context of TRADD

• Endogenous TRADD coimmunoprecipitated with K18, and colocalized with K8/18 filaments in human mammary epithelial cells [14].
• An increased constitutive expression of TNFRI and TRADD and decreased expression of TNFRII and TRAF-2 were observed in lymphocytes from aged as compared with young controls [15].
• FADD-DD provides the site of FADD recruitment to death receptor complexes at the plasma membrane by, for example, interaction with the Fas receptor cytoplasmic death domain (Fas-DD), or binding of the TNF-R1 adapter molecule TRADD [16].
• In untreated cells, in which TNF-R1 is found on the cell surface but principally localizes to the trans-Golgi network, TRADD is concentrated in the cis- or medial-Golgi region, but separates from the Golgi during cell fractionation [17].
• The subcellular interactions of TNF-R1 and the TRADD (TNFR-associated death domain protein) adaptor protein have been analyzed in the human monocyte cell line U937 and the human endothelial cell line ECV304 by confocal immunofluorescence microscopy and by Western blot analysis of fractionated cell extracts [17].

Associations of TRADD with chemical compounds

• We also show that RIP is a serine-threonine kinase that is recruited by TRADD to TNFR1 in a TNF-dependent process [10].
• We also showed that overexpressed NH2 termini of K18 and K8/18 were associated with endogenous TRADD in SW13 cells, resulting in the inhibition of caspase-8 activation [14].
• TRADD was the only protein that interacted with wild-type TES2 and not with isoleucine-mutated TES2 [18].
• In combination with TNF-alpha, however, ceramide potentiated, whereas NO inhibited, TNF-alpha-induced TRADD recruitment and caspase 8 activity [19].
• Treatment with 10(-7) M ICI or 10(-7) M Tam leads to a time dependent increase of TNFR1 and TRADD steady-state mRNA levels in MCF-7 cells [20].

Physical interactions of TRADD

• The COOH-terminal region of TRADD interacted with the coil Ia of the rod domain of K18 [14].
• DR6 interacts with TRADD, which has previously been shown to associate with TNFR1 [21].
• Our results indicate that PAK4 is required for optimal binding of the scaffold protein TRADD to the activated TNFalpha receptor through both kinase-dependent and kinase-independent mechanisms [22].
• Using this method, we identified mutations in FADD that prevent binding to Fas but do not affect binding to TRADD [23].
• Our in vivo data show that HCV core and TRADD form a ternary complex with TNFR1 [24].

Regulatory relationships of TRADD

• Members of the tumor necrosis factor receptor superfamily induce apoptosis via interaction with FADD and regulate cell growth and differentiation through TRADD and TRAFs molecules [25].
• Keratin attenuates tumor necrosis factor-induced cytotoxicity through association with TRADD [14].
• The signaling adaptors TRADD and RIP were also found to be necessary for ligand-induced RhoA activation [26].
• We show here that the zinc finger protein A20 is an NF-kappaB-inducible gene that can protect the IKKgamma-deficient cells from TNF-induced apoptosis by disrupting the recruitment of the death domain signaling molecules TRADD and RIP to the receptor signaling complex [27].
• EMAP-II facilitates TNF-R1 apoptotic signalling in endothelial cells and induces TRADD mobilization [28].

Other interactions of TRADD

• Furthermore, TNF-dependent recruitment of TRADD to surface TNFR1 was also inhibited [29].
• Overexpression of TRAF1, however, had no effect on the interaction of TRADD and TRAF2, known to be important for tumor necrosis factor receptor 1 (TNF-R1)-mediated NF-kappaB activation [30].
• Here we describe that HIPK2 can also associate with TRADD, a protein that interacts with tumor necrosis factor receptor type 1 (TNF-R1) [31].
• Among IF proteins tested in two-hybrid systems, TRADD specifically bound K18 and K14, type I (acidic) keratins [14].
• Stat1 as a component of tumor necrosis factor alpha receptor 1-TRADD signaling complex to inhibit NF-kappaB activation [32].

Analytical, diagnostic and therapeutic context of TRADD

• In addition, confocal microscopy indicated that NGF stimulation induced the plasma membrane localization of TRADD [5].
• These findings generate interest in utilizing TRADD in gene therapy for GM tumors, particularly in light of its dual function of directly inducing rapid apoptosis and sensitizing GM cells to standard anti-neoplastic therapy [33].
• Assignment of TRADD to human chromosome band 16q22 by in situ hybridization [34].

References