論文

査読有り 国際誌
2020年9月

G-CSF-dependent neutrophil differentiation requires downregulation of MAPK activities through the Gab2 signaling pathway.

Cell biology international
  • Xianglin Zhao
  • ,
  • Shun-Ichiro Kawano
  • ,
  • Junko Masuda
  • ,
  • Hiroshi Murakami

44
9
開始ページ
1919
終了ページ
1933
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1002/cbin.11398

Granulocyte colony-stimulating factor (G-CSF) stimulation of myeloid cells induced tyrosine-phosphorylation of cellular proteins. One of the tyrosine-phosphorylated proteins was found to be a scaffold protein, Grb2-associated binding protein 2 (Gab2). Another member of Gab family protein, Gab3, was exogenously overexpressed in neutrophil progenitor cells to make the Gab3 protein to compete with the endogenous Gab2 for the G-CSF-dependent signaling. In Gab3-overexpressed cells, the level of tyrosine phosphorylation of endogenous Gab2 by G-CSF stimulation was markedly downregulated, while the phosphorylation of Gab3 was significantly enhanced. The Gab3-overexpressed cells continuously proliferated in the medium containing G-CSF and lost the ability to differentiate to the mature neutrophil, characterized by the lobulated nucleus. The G-CSF stimulation-dependent tyrosine phosphorylation of Gab3, the association of SHP2 to Gab3 and the following mitogen-activated protein kinase (MAPK) activation were prolonged in the Gab3-overexpressed cells, compared to the parental cells, where the binding of SHP2 to Gab2 protein and thereby the activation of MAPK were not sustained after G-CSF stimulation. Inhibition of MAPK by pharmaceutical inhibitor restored the Gab3-overexpressed cells to the ability to differentiate to mature neutrophil. Therefore, G-CSF-dependent Gab2 phosphorylation and following its downregulation led the short-term MAPK activation. The downregulation of MAPK after transient Gab2 phosphorylation was necessary for the consequent neutrophil differentiation induced by G-CSF stimulation.

リンク情報
DOI
https://doi.org/10.1002/cbin.11398
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/32437087

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