2012 Fiscal Year Final Research Report
Novel functions and regulatory mechanisms of tumor suppressor Mig-6
| Project/Area Number |
22300329
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Tumor biology
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| Research Institution | Hamamatsu University School of Medicine |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
MATSUMOTO Masaki 九州大学, 生体防御医学研究所, 准教授 (60380531)
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| Project Period (FY) |
2010 – 2012
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| Keywords | リン酸化 / シグナル伝達 / 細胞増殖 |
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| Research Abstract |
Mig-6 acts as an inhibitor of EGF signaling via binding with the EGF receptor (EGFR). Downregulated expression of the Mig-6 gene is observed in breast carcinomas, in which it correlates with reduced overall survival. Mig-6-deficient mice show hyperactivation of endogenous EGFR and develop spontaneous tumors in various organs. Therefore, Mig-6 is an important tumor suppressor. However, its post-translational 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 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 a positive regulator of EGF signaling. This is a novel function of Chk1.
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