BACKGROUND Asparaginyl endopeptidase (AEP) has been implicated in human cancer development. However, the molecular mechanisms underlying AEP regulation, including the role of pro-AEP activation, remain elusive. METHODS We investigated the regulation of AEP by TRAF6 and its effects on tumor progression and metastasis in cancer cell lines, murine models, and specimens from patients using bioche...

TNF receptor superfamily members, such as CD40 and the Toll-like receptors (TLRs), regulate many aspects of B cell differentiation and activation. TRAF6 is an intracellular signaling adaptor molecule for these receptors, but its role in B cells has not been clarified by previous genetic approaches, as the systemic deletion of the TRAF6 gene results in perinatal lethality. Here we show that B ce...

TNF receptor-associated factor 6 (TRAF6) is a key hub protein involved in Toll-like receptor-dependent inflammatory signaling pathway, and it recruits additional proteins to form multiprotein complexes capable of activating downstream NF-κB inflammatory signaling pathway. Ubiquitin-proteasome system (UPS) plays a crucial role in various protein degradations, such as TRAF6, leading to inhibitory...

NF-kappaB Essential MOdulator (NEMO) has been shown to play a critical role in NF-kappaB activation, as the regulatory subunit of IkappaB kinase. Upon cell stimulation, NEMO can be modified through phosphorylation, sumoylation or ubiquitination. In the latter case, not much is known regarding the exact function of this posttranslational modification. One of the E3 ligase responsible for K63-lin...

Neurotrophin signaling through the p75 receptor regulates apoptosis within the nervous system both during development and in response to injury. Whereas a number of p75 interacting factors have been identified, how these upstream factors function in a coordinated manner to mediate receptor signaling is still unclear. Here, we report a functional interaction between TRAF6 and the neurotrophin re...

RANK and CD40 activate NF-kappaB and MAPKs to similar levels via TRAF6. Even though overexpression of TRAF6 results in osteoclast formation, RANK but not CD40 promotes osteoclastogenesis. To understand the molecular basis for RANK-specific activity in osteoclastogenesis, we created an osteoclast formation system driven by anti-human CD40 antibody-mediated stimulation of a chimeric receptor, h40...

Bortezomib (Velcade) is used widely for the treatment of various human cancers; however, its mechanisms of action are not fully understood, particularly in myeloid malignancies. Bortezomib is a selective and reversible inhibitor of the proteasome. Paradoxically, we find that bortezomib induces proteasome-independent degradation of the TRAF6 protein, but not mRNA, in myelodysplastic syndrome (MD...

صلاخلا ـ ة : ُّ دعتُ ل ثم ةيعيبطلا تاغللا ةجلاعم تاقيبطت نم ديدعلل ايساسأ انوكم ةيعوضوملا ةئزجتلا قيبطت تامولعملا عاجرتساو صوصنلا صيخلت . نم فدهلا وه ثحبلا اذ ه قت و مي ةيعوضوملا ة ئزجتلا تا يمزراوخ ة يلاعف ضوملا دودحلا ى لع فرعتلا يف ة يبرعلا صوصنلا لخاد ةيعو . م تو قايس لا اذ ه يف ة فلتخم رداصم نم ةيبرع صوصن ةسمخ لخاد اهنوظحلاي يتلا ةركفلا وأ عوضوملا تاريغت ىلع فرعتلل ةيبرعلا ةغللا ءارق نم ة...

Signal transduction pathways regulating NF-kappaB activation essential for microenvironment formation in secondary lymphoid organs remain to be determined. We investigated the effect of a deficiency of TNFR-associated factor 6 (TRAF6), which activates the classical NF-kappaB pathway, in splenic microenvironment formation. Two-week-old TRAF6-deficient mice showed severe defects in B cell follicl...