核因子-κB诱导激酶通过磷酸化丝氨酸176激活IKK-α。
NF-kappaB-inducing kinase activates IKK-alpha by phosphorylation of Ser-176.
作者信息
Ling L, Cao Z, Goeddel D V
机构信息
Tularik, Inc., Two Corporate Drive, South San Francisco, CA 94080, USA.
出版信息
Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3792-7. doi: 10.1073/pnas.95.7.3792.
Abstract
Activation of the transcription factor NF-kappaB by inflammatory cytokines involves the successive action of NF-kappaB-inducing kinase (NIK) and two IkappaB kinases, IKK-alpha and IKK-beta. Here we show that NIK preferentially phosphorylates IKK-alpha over IKK-beta, leading to the activation of IKK-alpha kinase activity. This phosphorylation of IKK-alpha occurs specifically on Ser-176 in the activation loop between kinase subdomains VII and VIII. A mutant form of IKK-alpha containing alanine at residue 176 cannot be phosphorylated or activated by NIK and acts as a dominant negative inhibitor of interleukin 1- and tumor necrosis factor-induced NF-kappaB activation. Conversely, a mutant form of IKK-alpha containing glutamic acid at residue 176 is constitutively active. Thus, the phosphorylation of IKK-alpha on Ser-176 by NIK may be required for cytokine-mediated NF-kappaB activation.
摘要
炎性细胞因子对转录因子NF-κB的激活涉及NF-κB诱导激酶（NIK）以及两种IκB激酶IKK-α和IKK-β的相继作用。我们在此表明，NIK对IKK-α的磷酸化作用优先于IKK-β，从而导致IKK-α激酶活性的激活。IKK-α的这种磷酸化作用特异性地发生在激酶亚结构域VII和VIII之间激活环中的丝氨酸176位点上。在第176位残基处含有丙氨酸的IKK-α突变形式不能被NIK磷酸化或激活，并作为白细胞介素1和肿瘤坏死因子诱导的NF-κB激活的显性负性抑制剂发挥作用。相反，在第176位残基处含有谷氨酸的IKK-α突变形式具有组成型活性。因此，NIK对IKK-α丝氨酸176位点的磷酸化作用可能是细胞因子介导的NF-κB激活所必需的。
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