Tyrosine Phosphorylation Is Required for I Kappa B Kinase-b (IKKb) Activation and Function in Osteoclastogenesis

• Published in: The Journal of biological chemistry 2010-08, Vol.285 (33), p.25522-25530
• Main Authors: Darwech, Isra, Otero, Jesse E, Alhawagri, Muhammad A, Abu-Amer, Yousef
• Format: Article
• Language: English
• ISSN: 0021-9258
• DOI: 10.1074/jbc.M110.121533

The transcription factor NF- Kappa B is crucial for numerous cellular functions such as survival, differentiation, immunity, and inflammation. A key function of this family of transcription factors is regulation of osteoclast differentiation and function, which in turn controls skeletal homeostasis. The I Kappa B kinase (IKK) complex, which contains IKKa, IKKb, and IKKg, is required for activation of NF- Kappa B, and deletion of either IKKa or IKKb resulted with defective osteoclast differentiation and survival. We have recently investigated the details of the mechanisms governing the role of IKKb in osteoclastogenesis and found that constitutively active IKKb in which serine residues 177/181 were mutated into negatively charged glutamic acids instigates spontaneous bona fide receptor activator of NF- Kappa B ligand (RANKL)-independent osteoclastogenesis. To better understand and define the functional role of IKKb domains capable of regulating the osteoclastogenic activity of IKK, we investigated key motifs in the activation T loop of IKKb, which are potentially capable of modulating its osteoclastogenic activity. We discovered that dual serine (traditional serine residues 177/181) and tyrosine (188/199) phosphorylation events are crucial for IKKb activation. Mutation of the latter tyrosine residues blunted the NF- Kappa B activity of wild type and constitutively active IKKb, and tyrosine 188/199-deficient IKKb inhibited osteoclastogenesis. Thus, tyrosines 188/199 are a novel target for regulating IKKb activity, at least in osteoclasts.