Durán Angeles, Serrano Manuel, Leitges Michael, Flores Juana M, Picard Sylvain, Brown Jacques P, Moscat Jorge, Diaz-Meco Maria T
Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma, Canto Blanco, 28049 Madrid, Spain.
Dev Cell. 2004 Feb;6(2):303-9. doi: 10.1016/s1534-5807(03)00403-9.
The atypical PKCs (aPKCs) have been implicated genetically in at least two independent signaling cascades that control NF-kappa B and cell polarity, through the interaction with the adapters p62 and Par-6, respectively. P62 binds TRAF6, which plays an essential role in osteoclastogenesis and bone remodeling. Recently, p62 mutations have been shown to be the cause of the 5q35-linked Paget's disease of bone, a genetic disorder characterized by aberrant osteoclastic activity. Here we show that p62, like TRAF6, is upregulated during RANK-L-induced osteoclastogenesis and that the genetic inactivation of p62 in mice leads to impaired osteoclastogenesis in vitro and in vivo, as well as inhibition of IKK activation and NF-kappa B nuclear translocation. In addition, RANK-L stimulation leads to the inducible formation of a ternary complex involving TRAF6, p62, and the aPKCs. These observations demonstrate that p62 is an important mediator during osteoclastogenesis and induced bone remodeling.
非典型蛋白激酶C（aPKCs）在基因层面上至少与两个独立的信号级联反应有关，这两个信号级联反应分别通过与衔接蛋白p62和Par-6相互作用来控制核因子κB（NF-κB）和细胞极性。p62与肿瘤坏死因子受体相关因子6（TRAF6）结合，TRAF6在破骨细胞生成和骨重塑过程中发挥着至关重要的作用。最近，p62突变已被证明是5q35连锁的佩吉特骨病的病因，这是一种以异常破骨细胞活性为特征的遗传性疾病。在此我们表明，与TRAF6一样，p62在核因子κB受体活化因子配体（RANK-L）诱导的破骨细胞生成过程中上调，并且小鼠体内p62的基因失活会导致体外和体内破骨细胞生成受损，以及抑制IκB激酶（IKK）激活和NF-κB核转位。此外，RANK-L刺激会导致形成一种涉及TRAF6、p62和aPKCs的诱导型三元复合物。这些观察结果表明，p62是破骨细胞生成和诱导性骨重塑过程中的重要介质。
