Integrin-linked kinase regulates chondrocyte shape and proliferation
Integrin-linked kinase regulates chondrocyte shape and proliferation
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DOI：
10.1038/sj.embor.embor801
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发表时间：
2003-04-01
期刊：
影响因子：
7.7
通讯作者：
Fässler, R
中科院分区：
文献类型：
--
作者：
Grashoff, C;Aszódi, A;Fässler, R
软骨细胞与细胞外基质环境的相互作用主要由整合素介导。连接的整联蛋白与支架蛋白和激酶如整联蛋白连接的激酶（Ilk）一起被募集至粘着斑（FA）。Ilk结合β 1-、β 2-和β 3-整联蛋白的胞质结构域并募集衔接子和激酶，并被认为通过蛋白激酶B/Akt（Pkb/Akt）和糖原合成酶激酶3-β（GSK 3-β）的磷酸化刺激下游信号传导事件。在这里，我们表明，小鼠与软骨细胞特异性破坏的基因编码ilk发展软骨发育不良，并死于出生时由于呼吸窘迫。软骨发育不良的特征是软骨细胞形状异常和软骨细胞增殖减少。此外，Ilk缺陷的软骨细胞表现出粘附缺陷，未能扩散，形成较少的脂肪酸和肌动蛋白应力纤维。令人惊讶的是，Pkb/Akt和GSK 3-β的磷酸化在Ilk缺陷的软骨细胞中不受影响。这些发现表明，Ilk调节软骨细胞中的肌动蛋白重组，并独立于Pkb/Akt和GSK 3-β的磷酸化来调节软骨细胞的生长。
The interaction of chondrocytes with the extracellular-matrix environment is mediated mainly by integrins. Ligated integrins are recruited to focal adhesions (FAs) together with scaffolding proteins and kinases, such as integrin-linked kinase (Ilk). Ilk binds the cytoplasmic domain of beta1-, beta2- and beta3-integrins and recruits adaptors and kinases, and is thought to stimulate downstream signalling events through phosphorylation of protein kinase B/Akt (Pkb/Akt) and glycogen synthase kinase 3-beta (GSK3-beta). Here, we show that mice with a chondrocyte-specific disruption of the gene encoding ilk develop chondrodysplasia, and die at birth due to respiratory distress. The chondrodysplasia was characterized by abnormal chondrocyte shape and decreased chondrocyte proliferation. In addition, Ilk-deficient chondrocytes showed adhesion defects, failed to spread and formed fewer FAs and actin stress fibres. Surprisingly, phosphorylation of Pkb/Akt and GSK3-beta is unaffected in Ilk-deficient chondrocytes. These findings suggest that Ilk regulates actin reorganization in chondrocytes and modulates chondrocyte growth independently of phosphorylation of Pkb/Akt and GSK3-beta.