2.3.2 Kinases MLKL (Mixed lineage kinase domain-like protein),
RIPK1 and RIPK3 (receptor-interacting protein kinases 1 and 3)
Annkathrin Koch et al 54 proposed that if
cystathionase was blocked with zVAD.fmk (TBZ), the combination therapy
of Smac mimicking BV6 and TRAIL induced BL necrotic apoptosis. The
higher the expression of MLKL (mixed lineage kinase domain-like
protein), the better the therapeutic effect of TBZ on BL cells,
confirming that MLKL expression is one of the influencing factors of TBZ
treatment on BL cells. Knockdown of MLKL in BL-2, RAMOS, Seraphine, and
BL-30 cells showed that cell death was completely inhibited, suggesting
that its mediated cell death was heavily dependent on MLKL. Necroptosis
is based on the generation of necrosome, the kinase MLKL, RIPK1 and
RIPK3 (receptor-interacting protein kinases 1 and 3) constitute the
necrosome 55, the place phosphorylation of MLKL and
RIPK1 is a necessary link in apoptosis. MLKL is a direct provider of
RIPK3 and its phosphorylation allows MLKL to oligomerize and translocate
at the plasma membrane, thereby binding it to the membrane and
inflicting its dying 56. In BL cell lines, expression
of TRAIL-R1/2 57, a Smac mimic that binds to TRAIL
(TNF-related apoptosis-inducing ligand), prompts
cysteinase-non-dependent necrotic cell dying in an MLKL-dependent manner
after cysteinase inhibition.