Prenylated PALM2 Promotes the Migration of Esophageal Squamous Cell Carcinoma Cells Through Activating Ezrin

Dan-Xia Deng; Cheng-Yu Li; Zhen-Yuan Zheng; Bing Wen; Lian-Di Liao; Xiao-Jun Zhang; En-Min Li; Li-Yan Xu

doi:10.1016/j.mcpro.2023.100593

Prenylated PALM2 Promotes the Migration of Esophageal Squamous Cell Carcinoma Cells Through Activating Ezrin

Mol Cell Proteomics. 2023 Aug;22(8):100593. doi: 10.1016/j.mcpro.2023.100593. Epub 2023 Jun 15.

Authors

Dan-Xia Deng¹, Cheng-Yu Li², Zhen-Yuan Zheng², Bing Wen³, Lian-Di Liao¹, Xiao-Jun Zhang⁴, En-Min Li⁵, Li-Yan Xu⁶

Affiliations

¹ Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Shantou University Medical College, Shantou, Guangdong, China.
² Department of Biochemistry and Molecular Biology, The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, China; Guangdong Esophageal Cancer Research Institute, Shantou Sub-center, Cancer Research Cancer, Shantou University Medical College, Shantou, Guangdong, China.
³ Department of Biochemistry and Molecular Biology, The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, China.
⁴ Central Laboratory, Shantou University Medical College, Shantou, Guangdong, China.
⁵ Department of Biochemistry and Molecular Biology, The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong, China. Electronic address: nmli@stu.edu.cn.
⁶ Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Institute of Oncologic Pathology, Shantou University Medical College, Shantou, Guangdong, China; Guangdong Esophageal Cancer Research Institute, Shantou Sub-center, Cancer Research Cancer, Shantou University Medical College, Shantou, Guangdong, China. Electronic address: lyxu@stu.edu.cn.

Abstract

Proteins containing a CAAX motif at the C-terminus undergo prenylation for localization and activity and include a series of key regulatory proteins, such as RAS superfamily members, heterotrimeric G proteins, nuclear lamina protein, and several protein kinases and phosphatases. However, studies of prenylated proteins in esophageal cancer are limited. Here, through research on large-scale proteomic data of esophageal cancer in our laboratory, we found that paralemmin-2 (PALM2), a potential prenylated protein, was upregulated and associated with poor prognosis in patients. Low-throughput verification showed that the expression of PALM2 in esophageal cancer tissues was higher than that in their paired normal esophageal epithelial tissues, and it was generally expressed in the membrane and cytoplasm of esophageal cancer cells. PALM2 interacted with the two subunits of farnesyl transferase (FTase), FNTA and FNTB. Either the addition of an FTase inhibitor or mutation in the CAAX motif of PALM2 (PALM2^C408S) impaired its membranous localization and reduced the membrane location of PALM2, indicating PALM2 was prenylated by FTase. Overexpression of PALM2 enhanced the migration of esophageal squamous cell carcinoma cells, whereas PALM2^C408S lost this ability. Mechanistically, PALM2 interacted with the N-terminal FERM domain of ezrin of the ezrin/radixin/moesin (ERM) family. Mutagenesis indicated that lysine residues K253/K254/K262/K263 in ezrin's FERM domain and C408 in PALM2's CAAX motif were important for PALM2/ezrin interaction and ezrin activation. Knockout of ezrin prevented enhanced cancer cell migration by PALM2 overexpression. PALM2, depending on its prenylation, increased both ezrin membrane localization and phosphorylation of ezrin at Y146. In summary, prenylated PALM2 enhances the migration of cancer cells by activating ezrin.

Keywords: PALM2; cell migration; esophageal squamous cell carcinoma; ezrin; prenylation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Movement
Esophageal Neoplasms* / metabolism
Esophageal Squamous Cell Carcinoma*
Humans
Proteomics

Substances

ezrin
Palm2-AKAP2 fusion protein, human