The phosphorylation-specific association of STMN1 with GRP78 promotes breast cancer metastasis

Xia-Ying Kuang; He-Sheng Jiang; Kai Li; Yi-Zi Zheng; Yi-Rong Liu; Feng Qiao; Shan Li; Xin Hu; Zhi-Ming Shao

doi:10.1016/j.canlet.2016.04.035

The phosphorylation-specific association of STMN1 with GRP78 promotes breast cancer metastasis

Cancer Lett. 2016 Jul 10;377(1):87-96. doi: 10.1016/j.canlet.2016.04.035. Epub 2016 Apr 26.

Authors

Xia-Ying Kuang¹, He-Sheng Jiang², Kai Li³, Yi-Zi Zheng², Yi-Rong Liu², Feng Qiao⁴, Shan Li⁴, Xin Hu⁵, Zhi-Ming Shao⁶

Affiliations

¹ Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Breast Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
² Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
³ Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
⁴ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
⁵ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Electronic address: xinhu@fudan.edu.cn.
⁶ Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Institutes of Biomedical Science, Fudan University, Shanghai, China. Electronic address: zhimingshao@yahoo.com.

PMID: 27130664
DOI: 10.1016/j.canlet.2016.04.035

Abstract

Metastasis is a major cause of death in patients with breast cancer. Stathmin1 (STMN1) is a phosphoprotein associated with cancer metastasis. It exhibits a complicated phosphorylation pattern in response to various extracellular signals, but its signaling mechanism is poorly understood. In this study, we report that phosphorylation of STMN1 at Ser25 and Ser38 is necessary to maintain cell migration capabilities and is associated with shorter disease-free survival (DFS) in breast cancer. In addition, we report that glucose-regulated protein of molecular mass 78 (GRP78) is a novel phospho-STMN1 binding protein upon STMN1 Ser25/Ser38 phosphorylation. This phosphorylation-dependent interaction is regulated by MEK kinase and is required for STMN1-GRP78 complex stability and STMN1-mediated migration. We also propose a prognostic model based on phospho-STMN1 and GRP78 to assess metastatic risk in breast cancer patients.

Keywords: Breast cancer; GRP78; Metastasis; Phosphorylation; Stathmin.

MeSH terms

Animals
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism*
Breast Neoplasms / genetics
Breast Neoplasms / metabolism*
Breast Neoplasms / mortality
Breast Neoplasms / pathology
Cell Line, Tumor
Cell Movement*
Decision Support Techniques
Disease-Free Survival
Endoplasmic Reticulum Chaperone BiP
Female
Heat-Shock Proteins / genetics
Heat-Shock Proteins / metabolism*
Humans
Kaplan-Meier Estimate
Lung Neoplasms / genetics
Lung Neoplasms / metabolism*
Lung Neoplasms / mortality
Lung Neoplasms / secondary
MAP Kinase Kinase Kinases / metabolism
Mice, Nude
Neoplasm Invasiveness
Neoplasm Staging
Phosphorylation
Proportional Hazards Models
Protein Binding
RNA Interference
Risk Assessment
Risk Factors
Serine
Signal Transduction
Stathmin / genetics
Stathmin / metabolism*
Time Factors
Transfection

Substances

Biomarkers, Tumor
Endoplasmic Reticulum Chaperone BiP
HSPA5 protein, human
Heat-Shock Proteins
Hspa5 protein, mouse
STMN1 protein, human
Stathmin
Serine
MAP Kinase Kinase Kinases