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 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.

• Authors: Kyung Ho Lee, Jeong-Ah Hwang, Sun-Ok Kim, Jung Hee Kim, Sang Chul Shin, Eunice EunKyeong Kim, Kyung S Lee, Kunsoo Rhee, Byeong Hwa Jeon, Jeong Kyu Bang, Hyunjoo Cha-Molstad, Nak-Kyun Soung, Jae-Hyuk Jang, Sung-Kyun Ko, Hee Gu Lee, Jong Seog Ahn, Yong Tae Kwon, Bo Yeon Kim
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 293 Issue 3 Pg. 847-862 (01 19 2018) ISSN: 1083-351X [Electronic] United States
• PMID: 29191835 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Adaptor Proteins, Signal Transducing
• Cell Cycle Proteins
• NEDD9 protein, human
• Phosphoproteins
• Proto-Oncogene Proteins
• Protein Serine-Threonine Kinases

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Cell Cycle Proteins (genetics, metabolism)
• Cell Line
• Cell Proliferation (genetics, physiology)
• Focal Adhesions (genetics, metabolism)
• HeLa Cells
• Humans
• Immunoblotting
• Immunoprecipitation
• Phosphoproteins (genetics, metabolism)
• Phosphorylation (genetics, physiology)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Proto-Oncogene Proteins (genetics, metabolism)
• Polo-Like Kinase 1