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

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. © 2020 International Federation for Cell Biology.

Citation

Xianglin Zhao, Shun-Ichiro Kawano, Junko Masuda, Hiroshi Murakami. G-CSF-dependent neutrophil differentiation requires downregulation of MAPK activities through the Gab2 signaling pathway. Cell biology international. 2020 Sep;44(9):1919-1933

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PMID: 32437087

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