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Phosphorylation of human enhancer filamentation 1 (HEF1) stimulates interaction with Polo-like kinase 1 leading to HEF1 localization to focal adhesions.


ABSTRACT: 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 1? (CK1?) 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.

SUBMITTER: Lee KH 

PROVIDER: S-EPMC5777258 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Phosphorylation of human enhancer filamentation 1 (HEF1) stimulates interaction with Polo-like kinase 1 leading to HEF1 localization to focal adhesions.

Lee Kyung Ho KH   Hwang Jeong-Ah JA   Kim Sun-Ok SO   Kim Jung Hee JH   Shin Sang Chul SC   Kim Eunice EunKyeong EE   Lee Kyung S KS   Rhee Kunsoo K   Jeon Byeong Hwa BH   Bang Jeong Kyu JK   Cha-Molstad Hyunjoo H   Soung Nak-Kyun NK   Jang Jae-Hyuk JH   Ko Sung-Kyun SK   Lee Hee Gu HG   Ahn Jong Seog JS   Kwon Yong Tae YT   Kim Bo Yeon BY  

The Journal of biological chemistry 20171130 3


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 Plk  ...[more]

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