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Chk1 phosphorylates the tumour suppressor Mig‐6, regulating the activation of EGF signalling
Author(s) -
Liu Ning,
Matsumoto Masaki,
Kitagawa Kyoko,
Kotake Yojiro,
Suzuki Sayuri,
Shirasawa Senji,
Nakayama Keiichi I,
Nakanishi Makoto,
Niida Hiroyuki,
Kitagawa Masatoshi
Publication year - 2012
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2012.88
Subject(s) - biology , phosphorylation , suppressor , microbiology and biotechnology , signal transduction , signalling , cancer research , genetics , cancer
The tumour suppressor gene product Mig‐6 acts as an inhibitor of epidermal growth factor (EGF) signalling. However, its posttranslational modifications and regulatory mechanisms have not been elucidated. Here, we investigated the phosphorylation of human Mig‐6 and found that Chk1 phosphorylated Mig‐6 in vivo as well as in vitro . Moreover, EGF stimulation promoted phosphorylation of Mig‐6 without DNA damage and the phosphorylation was inhibited by depletion of Chk1. EGF also increased Ser280‐phosphorylated Chk1, a cytoplasmic‐tethering form, via PI3K pathway. Mass spectrometric analyses suggested that Ser 251 of Mig‐6 was a major phosphorylation site by Chk1 in vitro and in vivo . Substitution of Ser 251 to alanine increased inhibitory activity of Mig‐6 against EGF receptor (EGFR) activation. Moreover, EGF‐dependent activation of EGFR and cell growth were inhibited by Chk1 depletion, and were rescued by co‐depletion of Mig‐6. Our results suggest that Chk1 phosphorylates Mig‐6 on Ser 251, resulting in the inhibition of Mig‐6, and that Chk1 acts as a positive regulator of EGF signalling. This is a novel function of Chk1.