Integrin-linked kinase is an adaptor with essential functions during mouse development
Integrin-linked kinase is an adaptor with essential functions during mouse development
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DOI：
10.1038/nature08468
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发表时间：
2009-10-15
期刊：
影响因子：
64.8
通讯作者：
Faessler, Reinhard
中科院分区：
文献类型：
--
作者：
Lange, Anika;Wickstroem, Sara A.;Faessler, Reinhard
多细胞生物的发育需要整合素介导的细胞与细胞外环境之间的相互作用。整合素与细胞外基质结合可催化多蛋白复合物的组装，从而传递调节细胞生理许多方面的机械和化学信号（1,2）。整合素连接激酶（Ilk）是一种多功能蛋白，结合β -整合素细胞质结构域，并通过招募α和β -parvin等肌动蛋白结合调节蛋白来调节肌动蛋白动力学(3)。Ilk也被证明具有丝氨酸/苏氨酸激酶活性(4)，并在哺乳动物细胞中磷酸化信号蛋白，如Akt1和糖原合成酶激酶3 β (Gsk3 β) (5)；然而，遗传学研究表明，这些功能在果蝇和蠕虫中并不存在（6,7）。在这里，我们发现在假定的激酶结构域的自磷酸化位点和pleckstrin同源结构域携带点突变的小鼠是正常的。相反，在激酶结构域潜在的atp结合位点（介导Ilk与α -parvin结合）的保守赖氨酸残基发生点突变的小鼠，会因肾发育不全而死亡。在α -parvin缺失的小鼠中也会出现类似的肾缺陷。因此，我们提供了遗传证据，表明Ilk的激酶活性对哺乳动物的发育是必不可少的；然而，Ilk和α -parvin之间的相互作用对肾脏发育至关重要。
The development of multicellular organisms requires integrin-mediated interactions between cells and their extracellular environment. Integrin binding to extracellular matrix catalyses assembly of multiprotein complexes, which transduce mechanical and chemical signals that regulate many aspects of cell physiology(1,2). Integrin-linked kinase (Ilk) is a multifunctional protein that binds beta-integrin cytoplasmic domains and regulates actin dynamics by recruiting actin binding regulatory proteins such as alpha-and beta-parvin(3). Ilk has also been shown to possess serine/threonine kinase activity(4) and to phosphorylate signalling proteins such as Akt1 and glycogen synthase kinase 3 beta (Gsk3 beta) in mammalian cells(5); however, these functions have been shown by genetic studies(6,7) not to occur in flies and worms. Here we show that mice carrying point mutations in the proposed autophosphorylation site of the putative kinase domain and in the pleckstrin homology domain are normal. In contrast, mice with point mutations in the conserved lysine residue of the potential ATP-binding site of the kinase domain, which mediates Ilk binding to alpha-parvin, die owing to renal agenesis. Similar renal defects occur in alpha-parvin-null mice. Thus, we provide genetic evidence that the kinase activity of Ilk is dispensable for mammalian development; however, an interaction between Ilk and alpha-parvin is critical for kidney development.