CDK5 is a major regulator of the tumor suppressor DLC1.
CDK5 is a major regulator of the tumor suppressor DLC1.
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DOI：
10.1083/jcb.201405105
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发表时间：
2014-12-08
期刊：
影响因子：
--
通讯作者：
Lowy DR
中科院分区：
文献类型：
--
作者：
Tripathi BK;Qian X;Mertins P;Wang D;Papageorge AG;Carr SA;Lowy DR
CDK5通过磷酸化和减弱DLC1的自抑制区域与其Rho-Gap结构域的结合来激活肿瘤抑制基因DLC1，并使其定位于局部粘连。DLC1是一种肿瘤抑制蛋白，其全部活性取决于它在局部粘连中的存在，它的Rho-GTP酶激活蛋白(Rho-GAP)功能，以及它与包括张力蛋白和Talin在内的几种配体的结合能力。然而，监管和协调这些活动的机制仍然知之甚少。在这里，我们确定CDK5，一个主要是细胞质的丝氨酸/苏氨酸激酶，是DLC1功能的重要调节因子。CDK5激酶将位于DLC1 N端的四个丝氨酸磷酸化到Rho-GAP结构域。当没有被磷酸化时，这个N-末端区域作为一个自我抑制结构域，通过有效地与Rho-GAP结构域结合，将DLC1置于封闭的非活性构象中。CDK5的磷酸化减少了这种结合，并协调了配位激活DLC1，包括它对焦点粘连的定位，它的Rho-Gap活性，以及它与张力蛋白和Talin结合的能力。在癌症中，CDK5的这些抗肿瘤作用可以为肿瘤中常见的DLC1的下调提供选择性压力，并可能有助于CDK5在肺腺癌中的促肿瘤活性。
CDK5 activates the tumor suppressor DLC1 by phosphorylating and diminishing the binding of an autoinhibitory region of DLC1 to its Rho-GAP domain and allows it to localize to focal adhesions. DLC1 is a tumor suppressor protein whose full activity depends on its presence at focal adhesions, its Rho–GTPase activating protein (Rho-GAP) function, and its ability to bind several ligands, including tensin and talin. However, the mechanisms that regulate and coordinate these activities remain poorly understood. Here we identify CDK5, a predominantly cytoplasmic serine/threonine kinase, as an important regulator of DLC1 functions. The CDK5 kinase phosphorylates four serines in DLC1 located N-terminal to the Rho-GAP domain. When not phosphorylated, this N-terminal region functions as an autoinhibitory domain that places DLC1 in a closed, inactive conformation by efficiently binding to the Rho-GAP domain. CDK5 phosphorylation reduces this binding and orchestrates the coordinate activation DLC1, including its localization to focal adhesions, its Rho-GAP activity, and its ability to bind tensin and talin. In cancer, these anti-oncogenic effects of CDK5 can provide selective pressure for the down-regulation of DLC1, which occurs frequently in tumors, and can contribute to the pro-oncogenic activity of CDK5 in lung adenocarcinoma.
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影响因子：
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作者：
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