The LIM protein, LIMD1, regulates AP-1 activation through an interaction with TRAF6 to influence osteoclast development
The LIM protein, LIMD1, regulates AP-1 activation through an interaction with TRAF6 to influence osteoclast development
复制标题
DOI：
10.1074/jbc.m607399200
复制
发表时间：
2007-01-05
影响因子：
4.8
通讯作者：
Longmore, Gregory D.
中科院分区：
文献类型：
--
作者：
Feng, Yunfeng;Zhao, Haibo;Longmore, Gregory D.
越来越多的在调节骨破骨细胞发育中起重要作用的蛋白质已被证明主要影响在生理或病理应激条件下的破骨细胞生成。为什么基础破骨细胞生成是正常的，以及这些蛋白如何调节应激破骨细胞生成反应，而不是基础破骨细胞生成，目前尚不清楚。Ajuba/Zyxin家族的LIM蛋白定位于细胞粘附的细胞位点，在那里它们有助于调节细胞粘附和迁移，转运到细胞核，在那里它们可以影响细胞的命运，但也发现在细胞质中，它们的功能在很大程度上是未知的。我们发现LIM蛋白家族的一个成员Limd1在破骨细胞分化过程中被上调，并与Traf6相互作用，Traf6是rank - l调节的破骨细胞发育的关键细胞质调节因子。Limd1正向影响Traf6激活AP-1的能力，Limd1（-/-）破骨前体细胞在激活AP-1从而诱导NFAT2时存在缺陷。Limd1（-/-）小鼠虽然具有正常的基础破骨细胞数量和骨密度，但对生理性和病理性破骨细胞刺激具有抗性。这些结果暗示Limd1可能是应激条件下破骨细胞发育的重要调节因子。
Increasingly a number of proteins important in the regulation of bone osteoclast development have been shown primarily influence osteoclastogenesis under conditions of physiologic or pathologic stress. Why basal osteoclastogenesis is normal and how these proteins regulate stress osteoclastogenic responses, as opposed to basal osteoclastogenesis, is unclear. LIM proteins of the Ajuba/Zyxin family localize to cellular sites of cell adhesion where they contribute to the regulation of cell adhesion and migration, translocate into the nucleus where they can affect cell fate, but are also found in the cytoplasm where their function is largely unknown. We show that one member of this LIM protein family, Limd1, is uniquely up-regulated during osteoclast differentiation and interacts with Traf6, a critical cytosolic regulator of RANK-L-regulated osteoclast development. Limd1 positively affects the capacity of Traf6 to activate AP-1, and Limd1(-/-) osteoclast precursor cells are defective in the activation of AP-1 and thus induction of NFAT2. Limd1(-/-) mice, although having normal basal bone osteoclast numbers and bone density, are resistant to physiological and pathologic osteoclastogenic stimuli. These results implicate Limd1 as a potentially important regulator of osteoclast development under conditions of stress.