乳腺癌衍生的 K172N、D301V 突变可消除 Na+/H+ 交换体调节因子 1 对血小板衍生生长因子受体信号的抑制作用。

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

机构信息

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.

出版信息

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

DOI:10.1016/j.febslet.2013.08.026

PMID:24012959

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.

摘要

钠/氢交换体调节因子 1（NHERF1）是一种已知与许多癌症相关蛋白相互作用的支架蛋白。最近在乳腺癌细胞中发现了 nherf1 突变（K172N 和 D301V）。为了研究 NHERF1 的功能特性，分别在 SKMES-1 细胞中稳定表达野生型和癌症衍生的 nherf1 突变。NHERF1-wt 的过表达抑制了细胞的恶性表型，包括增殖、迁移和侵袭。nherf1 突变（K172N 和 D301V）通过影响 PTEN/NHERF1/PDGFRβ 复合物的形成，使 NHERF1 抑制 PDGF 诱导的 AKT 和 ERK 激活的功能完全或部分丧失，并减弱 NHERF1-wt 的肿瘤抑制作用，导致 NHERF1 功能丧失。这些结果进一步证明了乳腺癌衍生的 nherf1 突变（K172N 和 D301V）的功能后果，并提示 NHERF1 在肿瘤发生和发展中的因果作用。