Phosphorylation of human enhancer filamentation 1 (HEF1) stimulates interaction with Polo-like kinase 1 leading to HEF1 localization to focal adhesions.
Phosphorylation of human enhancer filamentation 1 (HEF1) stimulates interaction with Polo-like kinase 1 leading to HEF1 localization to focal adhesions.
复制标题
人类增强子丝1（HEF1）的磷酸化刺激了与类似Polo样激酶1的相互作用，从而导致HEF1定位与局灶性粘连。
DOI：
10.1074/jbc.m117.802587
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发表时间：
2018-01-19
期刊：
影响因子：
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通讯作者：
Kim BY
中科院分区：
文献类型：
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作者：
Lee KH;Hwang JA;Kim SO;Kim JH;Shin SC;Kim EE;Lee KS;Rhee K;Jeon BH;Bang JK;Cha-Molstad H;Soung NK;Jang JH;Ko SK;Lee HG;Ahn JS;Kwon YT;Kim BY
人增强子表达1（HEF 1;也称为NEDD 9或Cas-L）的表达升高是各种实体瘤转移过程的重要刺激。该过程需要HEF 1定位于粘着斑（FA）。尽管HEF 1与FA的结合被认为在癌细胞迁移中起作用，但靶向HEF 1与FA的机制仍不清楚。此外，Polo样激酶1（Plk 1）的上调与人类癌症转移呈正相关，但Plk 1的失调如何促进转移仍然是难以捉摸的。在这里，我们报告了酪蛋白激酶1δ（CK 1 δ）磷酸化HEF 1的Ser-780和Thr-804，这些磷酸化事件促进Plk 1和HEF 1之间的物理相互作用。我们发现，这种相互作用是至关重要的HEF 1易位到脂肪酸和诱导迁移的HeLa细胞。Plk 1对接磷酸化表位映射/确认HEF 1通过各种方法，包括X-射线晶体学，并在HeLa细胞中的功能分析突变。总之，我们的研究结果揭示了磷酸化依赖性HEF 1-Plk 1复合物在HEF 1转运至FA以诱导细胞迁移中的作用。我们的研究结果为HEF 1-Plk 1复合物依赖性定位于转移过程中的FA提供了重要的机制见解，因此可能有助于开发新的癌症治疗方法。
Elevated expression of human enhancer filamentation 1 (HEF1; also known as NEDD9 or Cas-L) is an essential stimulus for the metastatic process of various solid tumors. This process requires HEF1 localization to focal adhesions (FAs). Although the association of HEF1 with FAs is considered to play a role in cancer cell migration, the mechanism targeting HEF1 to FAs remains unclear. Moreover, up-regulation of Polo-like kinase 1 (Plk1) positively correlates with human cancer metastasis, yet how Plk1 deregulation promotes metastasis remains elusive. Here, we report that casein kinase 1δ (CK1δ) phosphorylates HEF1 at Ser-780 and Thr-804 and that these phosphorylation events promote a physical interaction between Plk1 and HEF1. We found that this interaction is critical for HEF1 translocation to FAs and for inducing migration of HeLa cells. Plk1-docking phosphoepitopes were mapped/confirmed in HEF1 by various methods, including X-ray crystallography, and mutated for functional analysis in HeLa cells. In summary, our results reveal the role of a phosphorylation-dependent HEF1–Plk1 complex in HEF1 translocation to FAs to induce cell migration. Our findings provide critical mechanistic insights into the HEF1–Plk1 complex–dependent localization of HEF1 to FAs underlying the metastatic process and may therefore contribute to the development of new cancer therapies.