The hCds1 (Chk2)-FHA domain is essential for a chain of phosphorylation events on hCds1 that is induced by ionizing radiation
The hCds1 (Chk2)-FHA domain is essential for a chain of phosphorylation events on hCds1 that is induced by ionizing radiation
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DOI：
10.1074/jbc.m104414200
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发表时间：
2001-08-10
影响因子：
4.8
通讯作者：
Chung, JH
中科院分区：
文献类型：
--
作者：
Lee, CH;Chung, JH
hCds 1（Chk 2）（1-4）是一种进化上保守的激酶，在DNA损伤反应和细胞周期检查点中发挥作用。激酶的Cds 1家族被大的磷脂酰肌醇3-激酶样激酶家族激活。在人类中，共济失调毛细血管扩张突变（ATM）（5）和共济失调毛细血管扩张和Rad 3相关（6）激酶通过磷酸化Thr（68）激活hCds 1（7-9）。hCds 1和Cds 1相关激酶含有FHA（fork.头相关）结构域（10），其似乎对于整合DNA损伤信号是重要的。目前尚不清楚ATM磷酸化如何激活hCds 1功能以及磷酸化是否与FHA相关。在这里，我们证明了hCds 1-FHA结构域是Thr（68）磷酸化所必需的。Thr（68）磷酸化反过来又是电离辐射诱导的hCds 1中两个氨基酸残基Thr（383）和Thr（387）的自磷酸化所必需的。这两个氨基酸残基位于hCds 1的活化环中，在hCds 1相关激酶中是保守的，并且对于hCds 1活性是必需的。因此，hCds 1-FRA结构域介导hCds 1上的磷酸化事件链，其包括响应于DNA损伤的ATM磷酸化和hCds 1自磷酸化。
hCds1 (Chk2) (1-4) is an evolutionarily conserved kinase that functions in DNA damage response and cell cycle checkpoint. The Cds1 family of kinases are activated by a family of large phosphatidylinositol 3-kinase-like kinases. In humans, ataxia telangiectasia-mutated (ATM) (5) and ataxia-telangiectasia and Rad3-related (6) kinases activate hCds1 by phosphorylating Thr(68) (7-9). hCds1 and Cds1-related kinases contain the FHA (fork. head-associated) domain (10), which appears to be important for integrating the DNA damage signal. It is not known how ATM phosphorylation activates hCds1 function and whether the phosphorylation is linked to the FHA. Here, we demonstrate that the hCds1-FHA domain is essential for Thr(68) phosphorylation. Thr(68) phosphorylation, in turn, is required for ionizing radiation-induced autophosphorylation of two amino acid residues in hCds1, Thr(383) and Thr(387). These two amino acid residues, located in the activation loop of hCds1, are conserved in hCds1-related kinases and are essential for hCds1 activity. Thus, the hCds1-FRA domain mediates a chain of phosphorylation events on hCds1, which includes phosphorylation by ATM and hCds1 autophosphorylation, in response to DNA damage.