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

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.
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https://www.hal.inserm.fr/inserm-02437732
Contributor : Anne-Odile Hueber <>
Submitted on : Monday, January 13, 2020 - 9:32:32 PM
Last modification on : Thursday, March 5, 2020 - 12:20:35 PM

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Aurélie Rossin, Nadia Lounnas, Jérome Durivault, Giorgia Miloro, Laurent Gagnoux-Palacios, et al.. The Btk-dependent PIP5K1γ lipid kinase activation by Fas counteracts FasL-induced cell death. Apoptosis, Springer Verlag, 2018, 22, pp.1344 - 1352. ⟨10.1007/s10495-017-1415-x⟩. ⟨inserm-02437732⟩

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