Swarnkar Gaurav, Karuppaiah Kannan, Mbalaviele Gabriel, Chen Tim Hung-Po, Abu-Amer Yousef
Department of Orthopaedic Surgery and Cell Biology & Physiology and.
Bone and Mineral Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110.
Proc Natl Acad Sci U S A. 2015 Jan 6;112(1):154-9. doi: 10.1073/pnas.1415213112. Epub 2014 Dec 22.
The MAP kinase TGFβ-activated kinase (TAK1) plays a crucial role in physiologic and pathologic cellular functions including cell survival, differentiation, apoptosis, inflammation, and oncogenesis. However, the entire repertoire of its mechanism of action has not been elucidated. Here, we found that ablation of Tak1 in myeloid cells causes osteopetrosis in mice as a result of defective osteoclastogenesis. Mechanistically, Tak1 deficiency correlated with increased NUMB-like (NUMBL) levels. Accordingly, forced expression of Numbl abrogated osteoclastogenesis whereas its deletion partially restored osteoclastogenesis and reversed the phenotype of Tak1 deficiency. Tak1 deletion also down-regulated Notch intracellular domain (NICD), but increased the levels of the transcription factor recombinant recognition sequence binding protein at Jκ site (RBPJ), consistent with NUMBL regulating notch signaling through degradation of NICD, a modulator of RBPJ. Accordingly, deletion of Rbpj partially corrected osteopetrosis in Tak1-deficient mice. Furthermore, expression of active IKK2 in RBPJ/TAK1-deficient cells significantly restored osteoclastogenesis, indicating that activation of NF-κB is essential for complete rescue of the pathway. Thus, we propose that TAK1 regulates osteoclastogenesis by integrating activation of NF-κB and derepression of NOTCH/RBPJ in myeloid cells through inhibition of NUMBL.
丝裂原活化蛋白激酶TGFβ激活激酶（TAK1）在包括细胞存活、分化、凋亡、炎症和肿瘤发生在内的生理和病理细胞功能中起着关键作用。然而，其作用机制的全貌尚未阐明。在这里，我们发现髓系细胞中Tak1的缺失会导致小鼠骨质石化，这是破骨细胞生成缺陷的结果。从机制上讲，Tak1缺乏与NUMB样（NUMBL）水平升高相关。因此，Numbl的强制表达消除了破骨细胞生成，而其缺失部分恢复了破骨细胞生成并逆转了Tak1缺乏的表型。Tak1缺失还下调了Notch细胞内结构域（NICD），但增加了转录因子重组识别序列结合蛋白Jκ位点（RBPJ）的水平，这与NUMBL通过降解RBPJ的调节剂NICD来调节Notch信号一致。因此，Rbpj的缺失部分纠正了Tak1缺陷小鼠的骨质石化。此外，在RBPJ/TAK1缺陷细胞中表达活性IKK2显著恢复了破骨细胞生成，表明NF-κB的激活对于该途径的完全挽救至关重要。因此，我们提出TAK1通过抑制NUMBL来整合髓系细胞中NF-κB的激活和NOTCH/RBPJ的去抑制，从而调节破骨细胞生成。
