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MEK2 is a critical modulating mechanism to down‐regulate GCIP stability and function in cancer cells
Author(s) -
Liang RueiYue,
Liu BangHung,
Huang ChihJou,
Lin KuanTing,
Ko ChihChung,
Huang LinLun,
Hsu Bin,
Wu ChunYing,
Chuang ShowMei
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201901911r
Subject(s) - carcinogenesis , downregulation and upregulation , cyclin d1 , cancer research , cancer , cell growth , ubiquitin , cancer cell , biology , microbiology and biotechnology , suppressor , mapk/erk pathway , signal transduction , cell cycle , biochemistry , genetics , gene
Loss of tumor suppressor activity and upregulation of oncogenic pathways simultaneously contribute to tumorigenesis. Expression of the tumor suppressor, GCIP (Grap2‐ and cyclin D1‐interacting protein), is usually reduced or lost in advanced cancers, as seen in both mouse tumor models and human cancer patients. However, no previous study has examined how cancer cells down‐regulate GCIP expression. In this study, we first validate the tumor suppressive function of GCIP using clinical gastric cancer tissues and online database analysis. We then reveal a novel mechanism whereby MEK2 directly interacts with and phosphorylates GCIP at its Ser313 and Ser356 residues to promote the turnover of GCIP by ubiquitin‐mediated proteasomal degradation. We also reveal that decreased GCIP stability enhances cell proliferation and promotes cancer cell migration and invasion. Taken together, these findings provide a more comprehensive view of GCIP in tumorigenesis and suggest that the oncogenic MEK/ERK signaling pathway negatively regulates the protein level of GCIP to promote cell proliferation and migration.