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Chk1 phosphorylates the tumour suppressor Mig-6, regulating the activation of EGF signalling

Ning Liu1, Masaki Matsumoto, Kyoko Kitagawa

  • 1Department of Molecular Biology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.

The EMBO Journal
|April 17, 2012
PubMed

Insights

The tumor suppressor Mig-6 inhibits epidermal growth factor (EGF) signaling. Checkpoint kinase 1 (Chk1) phosphorylates Mig-6, enhancing EGF receptor activity and cell growth.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Signal Transduction

Background:

  • Mig-6 is a tumor suppressor that inhibits epidermal growth factor (EGF) signaling.
  • The posttranslational modifications and regulatory mechanisms of Mig-6 are not fully understood.

Purpose of the Study:

  • To investigate the phosphorylation of human Mig-6.
  • To elucidate the role of Chk1 in Mig-6 regulation and EGF signaling.

Main Methods:

  • In vitro and in vivo phosphorylation assays using human Mig-6.
  • Epidermal growth factor (EGF) stimulation and Chk1 depletion experiments.
  • Mass spectrometry to identify phosphorylation sites.
  • Site-directed mutagenesis (Ser 251 to alanine).
  • Analysis of EGF receptor (EGFR) activation and cell growth.

Main Results:

  • Checkpoint kinase 1 (Chk1) phosphorylates Mig-6 in vitro and in vivo.
  • Epidermal growth factor (EGF) stimulation increases Mig-6 phosphorylation via the PI3K pathway, dependent on Chk1.
  • Serine 251 (Ser 251) was identified as a major Chk1 phosphorylation site on Mig-6.
  • Phosphorylation of Mig-6 at Ser 251 inhibits its suppressive activity on EGF receptor (EGFR) activation.
  • Chk1 depletion inhibits EGF-dependent EGFR activation and cell growth, which is rescued by Mig-6 co-depletion.

Conclusions:

  • Chk1 phosphorylates Mig-6 at Ser 251, leading to the inhibition of Mig-6's tumor suppressor function.
  • Chk1 acts as a positive regulator of EGF signaling by phosphorylating Mig-6.
  • This study reveals a novel function of Chk1 in regulating EGF signaling pathways.

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