Death-associated protein kinase 1 phosphorylates Pin1 and inhibits its prolyl isomerase activity and cellular function.
Death-associated protein kinase 1 phosphorylates Pin1 and inhibits its prolyl isomerase activity and cellular function.
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DOI：
10.1016/j.molcel.2011.03.005
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发表时间：
2011-04-22
期刊：
影响因子：
16
通讯作者：
Lu KP
中科院分区：
文献类型：
--
作者：
Lee TH;Chen CH;Suizu F;Huang P;Schiene-Fischer C;Daum S;Zhang YJ;Goate A;Chen RH;Zhou XZ;Lu KP
Pin1是一种磷酸专一性的脯氨酰异构酶，它调节许多关键的信号分子，它的失控导致疾病，尤其是癌症。然而，由于Prolyl异构酶通常被认为是结构性活性的，人们对Pin1催化活性是否以及如何调控知之甚少。在这里，我们确定死亡相关蛋白激酶1(DAPK1)是一种已知的肿瘤抑制因子，负责催化活性部位Ser71上Pin1的磷酸化。这种磷酸化完全失活Pin1的催化活性，并抑制其核定位。此外，DAPK1抑制Pin1诱导中心体扩增和细胞转化的能力。在乳腺癌中，Pin1 pSer71水平与DAPK1水平呈正相关，与中心体扩增呈负相关。因此，DAPK1对Pin1 Ser71的磷酸化抑制了其催化活性和细胞功能，为Pin1酶活性对其细胞功能的重要作用提供了强有力的证据。
Pin1 is a phospho-specific prolyl isomerase that regulates numerous key signaling molecules and whose deregulation contributes to disease notably cancer. However, since prolyl isomerases are often believed to be constitutively active, little is known whether and how Pin1 catalytic activity is regulated. Here we identify death associated protein kinase 1 (DAPK1), a known tumor suppressor, as a kinase responsible for phosphorylation of Pin1 on Ser71 in the catalytic active site. Such phosphorylation fully inactivates Pin1 catalytic activity and inhibits its nuclear location. Moreover, DAPK1 inhibits the ability of Pin1 to induce centrosome amplification and cell transformation. Finally, Pin1 pSer71 levels are positively correlated with DAPK1 levels and negatively with centrosome amplification in human breast cancer. Thus, phosphorylation of Pin1 Ser71 by DAPK1 inhibits its catalytic activity and cellular function, providing strong evidence for an essential role of the Pin1 enzymatic activity for its cellular function.
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影响因子：
21.3
作者：
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