RIPK1:RIPK3 oligomer binds MLKL

Stable Identifier
Reaction [binding]
Homo sapiens
Locations in the PathwayBrowser
SVG |   | PPTX  | SBGN
Click the image above or here to open this reaction in the Pathway Browser
The layout of this reaction may differ from that in the pathway view due to the constraints in pathway layout

Mixed lineage kinase domain-like protein (MLKL) was identified as an essential checkpoint for programmed necrosis. Knockdown of MLKL by shRNA in human colon adenocarcinoma (HT29) or gastric cancer MKN45 cells inhibited TNF alpha-induced necrosis (Sun L et al. 2012; Zhao J et al. 2012; Wang H et al. 2014). Treatment with the MLKL chemical inhibitor necrosulfonamide (NSA) also inhibited TNF-induced necrotic cell death in a variety of human cell lines, e.g., HT29 , FADD-null T cell leukemia Jurkat cells, pancreatic cancer Panc-1 cells (Sun L et al. 2012). As in humans, knockdown of MLKL or inhibition by NSA blocks TNF-induced necroptosis in mouse L929 fibrosarcoma cells (Sun L et al. 2012; Zhao J et al. 2012; Remijsen Q et al. 2014).

MLKL was found to interact with receptor interacting protein kinase 3 (RIPK3) when co-expressed in human embryonic kidney 293 (HEK293) cells (Zhao J et al. 2012). The C-terminal kinase-like domain of MLKL is responsible for association with RIPK3 (Sun L et al. 2012). MLKL-bound necrosome complex was reported to translocate to cell membrane systems (Wang Z et al. 2012; Chen X et al. 2014; Cai Z et al. 2014; Wang H et al. 2014). Translocation of MLKL to lipid rafts of the plasma membrane is thought to induce membrane permeability with subsequent loss of ionic homeostasis, which increases osmotic pressure, eventually leading to membrane rupture (Cai Z et al. 2014; Dondelinger Y et al. 2014).

Even though the Reactome annotation shows that 3 molecules of MLKL bind to the RIPK1:RIPK3 oligomer, the exact stoichiometry of the binding and the oligomerization of MLKL itself remains unclear (Chen X et al. 2014; Cai Z et al. 2014).

Literature References
PubMed ID Title Journal Year
22421439 Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis

Zhao, J, Jitkaew, S, Cai, Z, Choksi, S, Li, Q, Luo, J, Liu, ZG

Proc. Natl. Acad. Sci. U.S.A. 2012
22265413 Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase

Sun, L, Wang, H, Wang, Z, He, S, Chen, S, Liao, D, Wang, L, Yan, J, Liu, W, Lei, X, Wang, X

Cell 2012
Participant Of
Orthologous Events