The MEK-ERK-MST1 Axis Potentiates the Activation of the Extrinsic Apoptotic Pathway during GDC-0941 Treatment in Jurkat T Cells

Cells
Jana NovákováKarel Vališ

Abstract

The discrete activation of individual caspases is essential during T-cell development, activation, and apoptosis. Humans carrying nonfunctional caspase-8 and caspase-8 conditional knockout mice exhibit several defects in the progression of naive CD4⁺ T cells to the effector stage. MST1, a key kinase of the Hippo signaling pathway, is often presented as a substrate of caspases, and its cleavage by caspases potentiates its activity. Several studies have focused on the involvement of MST1 in caspase activation and also reported several defects in the immune system function caused by MST1 deficiency. Here, we show the rapid activation of the MEK-ERK-MST1 axis together with the cleavage and activation of caspase-3, -6, -7, -8, and -9 after PI3K signaling blockade by the selective inhibitor GDC-0941 in Jurkat T cells. We determined the phosphorylation pattern of MST1 using a phosphoproteomic approach and identified two amino acid residues phosphorylated in an ERK-dependent manner after GDC-0941 treatment together with a novel phosphorylation site at S21 residue, which was extensively phosphorylated in an ERK-independent manner during PI3K signaling blockade. Using caspase inhibitors and the inhibition of MST1 expression using siRNA, ...Continue Reading

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Citations

May 8, 2020·International Journal of Molecular Sciences·Karel Vališ, Petr Novák
Apr 17, 2021·Biochemical Society Transactions·Sofiia KarchuginaJonathan Chernoff

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Methods Mentioned

BETA
pull-down
transfection
co-immunoprecipitation
co-IP
immunoprecipitation

Software Mentioned

Skyline
ELM
GraphPad
Andromeda
Eukaryotic Linear Motif ( ELM )
Perseus
MaxQuant

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