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Apoptosis. 2017 Nov;22(11):1344-1352. doi: 10.1007/s10495-017-1415-x.

The Btk-dependent PIP5K1γ lipid kinase activation by Fas counteracts FasL-induced cell death.

Author information

1
Université Côte d'Azur, Institut de Biologie Valrose, CNRS UMR 7277, Inserm UMR 1091, Parc Valrose, Bâtiment des Sciences Naturelles, 06108, Nice Cedex2, France.
2
Université Côte d'Azur, Institut de Biologie Valrose, CNRS UMR 7277, Inserm UMR 1091, Parc Valrose, Bâtiment des Sciences Naturelles, 06108, Nice Cedex2, France. hueber@unice.fr.

Abstract

The Fas/FasL system plays a critical role in death by apoptosis and immune escape of cancer cells. The Fas receptor being ubiquitously expressed in tissues, its apoptotic-inducing function, initiated upon FasL binding, is tightly regulated by several negative regulatory mechanisms to prevent inappropriate cell death. One of them, involving the non-receptor tyrosine kinase Btk, was reported mainly in B cells and only poorly described. We report here that Btk negatively regulates, through its tyrosine kinase activity, the FasL-mediated cell death in epithelial cell lines from colon cancer origin. More importantly, we show that Btk interacts not only with Fas but also with the phosphatidylinositol-4-phosphate 5-kinase, PIP5K1γ, which, upon stimulation by Fas ligand, is responsible of a rapid and transient synthesis of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2). This production requires both the presence and the tyrosine kinase activity of Btk, and participates in the negative regulation of FasL-mediated cell death since knocking down PIP5K1γ expression significantly strengthens the apoptotic signal upon FasL engagement. Altogether, our data demonstrate the cooperative role of Btk and PIP5K1γ in a FasL-induced PI(4,5)P2 production, both proteins participating to the threshold setting of FasL-induced apoptotic commitment in colorectal cell lines.

KEYWORDS:

Btk; Cell death; Fas; PI(4,5)P2; PIP5K1γ

PMID:
28879546
DOI:
10.1007/s10495-017-1415-x
[Indexed for MEDLINE]

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