Its initiation, execution, and inhibition involve the expression and regulation of receptor interacting protein kinase 1 (RIPK1) and mixed lineage kinase
domain-like protein (MLKL).
Alcoholic cirrhosis is associated with necrotic hepatocyte cell death, called necroptosis , which is regulated by RIP1-RIP3-MLKL--(mixed lineage kinase
domain-like protein-) mediated necrotic cascade, but the role of RIPK1 and RIPK3 in the pathogeneses of alcoholic liver cirrhosis is largely unknown.
Wang et al., "Mixed lineage kinase
domain-like protein mediates necrosis signaling downstream of RIP3 kinase," Cell, vol.
MTK1, mixed lineage kinase
(MLK) 2/3, apoptosis signal-regulating kinase (ASK) 1, and transforming growth factor [beta]-activated kinase (TAK) 1 are all MKK kinases (MAP3Ks) that have been demonstrated to activate p38 signaling [47-54].
The mixed lineage kinase
domain like protein (MLKL) has been shown to be an important substrate of RIP3 likely targeting functional downstream targets on cellular organelles such as mitochondria and/or lysosomes .
Recently, exome sequencing of metastatic melanoma cells reveals somatic mutations in the genes encoding ASK1 and another MAP3K, mixed lineage kinase
1 (MLK1).107) In the prevalent screen, mutations in the protein-coding regions of ASK1 and MLK1 are found in 9% and 15% of 85 melanoma cell lines examined, respectively, and are almost mutually exclusive.