Breast cancer-derived K172N, D301V mutations abolish Na+/H+ exchanger regulatory factor 1 inhibition of platelet-derived growth factor receptor signaling

Shan Cheng; Yang Li; Ying Yang; Duiping Feng; Longyan Yang; Qian Ma; Shuai Zheng; Ran Meng; Shuhui Wang; Songlin Wang; Wen G Jiang; Junqi He

doi:10.1016/j.febslet.2013.08.026

Breast cancer-derived K172N, D301V mutations abolish Na+/H+ exchanger regulatory factor 1 inhibition of platelet-derived growth factor receptor signaling

FEBS Lett. 2013 Oct 11;587(20):3289-95. doi: 10.1016/j.febslet.2013.08.026. Epub 2013 Sep 5.

Authors

Shan Cheng¹, Yang Li, Ying Yang, Duiping Feng, Longyan Yang, Qian Ma, Shuai Zheng, Ran Meng, Shuhui Wang, Songlin Wang, Wen G Jiang, Junqi He

Affiliation

¹ Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing 100069, China; Capital Medical University-Cardiff University Joint Centre for Biomedical Research, Capital Medical University, Beijing 100069, China.

PMID: 24012959
DOI: 10.1016/j.febslet.2013.08.026

Abstract

Na(+)/H(+) exchanger regulatory factor 1 (NHERF1) is a scaffold protein known to interact with a number of cancer-related proteins. nherf1 Mutations (K172N and D301V) were recently identified in breast cancer cells. To investigate the functional properties of NHERF1, wild-type and cancer-derived nherf1 mutations were stably expressed in SKMES-1 cells respectively. NHERF1-wt overexpression suppressed the cellular malignant phenotypes, including proliferation, migration, and invasion. nherf1 Mutations (K172N and D301V) caused complete or partial loss of NHERF1 functions by affecting the PTEN/NHERF1/PDGFRβ complex formation, inactivating NHERF1 inhibition of PDGF-induced AKT and ERK activation, and attenuating the tumor-suppressor effects of NHERF1-wt. These results further demonstrated the functional consequences of breast cancer-derived nherf1 mutations (K172N and D301V), and suggested the causal role of NHERF1 in tumor development and progression.

Keywords: Breast cancer; EBP50; NHERF1; PDGFR; PDZ; PTEN.

Publication types

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

MeSH terms

Animals
Breast Neoplasms / genetics
Breast Neoplasms / metabolism*
COS Cells
Cell Line, Tumor
Cell Proliferation
Chlorocebus aethiops
Female
Humans
Mutation
PTEN Phosphohydrolase / genetics
PTEN Phosphohydrolase / metabolism
Phosphoproteins / genetics
Phosphoproteins / metabolism*
Protein Binding
Receptor, Platelet-Derived Growth Factor beta / genetics
Receptor, Platelet-Derived Growth Factor beta / metabolism*
Sodium-Hydrogen Exchangers / genetics
Sodium-Hydrogen Exchangers / metabolism*

Substances

Phosphoproteins
Sodium-Hydrogen Exchangers
sodium-hydrogen exchanger regulatory factor
Receptor, Platelet-Derived Growth Factor beta
PTEN Phosphohydrolase
PTEN protein, human