Mixed lineage kinase domain like pseudokinase

This gene belongs to the protein kinase superfamily. The encoded protein contains a protein kinase-like domain; however, is thought to be inactive because it lacks several residues required for activity. This protein plays a critical role in tumor necrosis factor (TNF)-induced necroptosis, a programmed cell death process, via interaction with receptor-interacting protein 3 (RIP3), which is a key signaling molecule in necroptosis pathway. Inhibitor studies and knockdown of this gene inhibited TNF-induced necrosis.

High levels of this protein and RIP3 are associated with inflammatory bowel disease in children. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Sep 2015]. A unique neurodegenerative disease has been reported in association with a homozygous frameshift mutation, rs561839347, in MLKL that causes replacement of part of the C-terminal pseudokinase domain with a 21-residue sequence of random amino acids.{{cite journal|vauthors=Faergeman SL, Evans H, Attfield KE, Desel C, Kuttikkatte SB, Sommerlund M, Jensen LT, Frokiaer J, Friese MA, Matthews PM, Luchtenborg C, Brügger B, Oturai AB, Dendrou CA, Fugger L|display-authors=6|title=A novel neurodegenerative spectrum disorder in patients with MLKL deficiency|journal=Cell Death & Disease|volume=11|issue=5|id=Art. No. 303|year=2020|page=303|doi=10.1038/s41419-020-2494-0|doi-access=free|pmid=32358523|pmc=7195448}}

• Necroptosis
• Cell death

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• {{cite journal |vauthors=Dastani Z, Pajukanta P, Marcil M, Rudzicz N, Ruel I, Bailey SD, Lee JC, Lemire M, Faith J, Platko J, Rioux J, Hudson TJ, Gaudet D, Engert JC, Genest J |title=Fine mapping and association studies of a high-density lipoprotein cholesterol linkage region on chromosome 16 in French-Canadian subjects |journal=Eur. J. Hum. Genet. |volume=18 |issue=3 |pages=342–7 |year=2010 |pmid=19844255 |pmc=2824775 |doi=10.1038/ejhg.2009.157 }}
• {{cite journal |vauthors=Sun L, Wang H, Wang Z, He S, Chen S, Liao D, Wang L, Yan J, Liu W, Lei X, Wang X |title=Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase |journal=Cell |volume=148 |issue=1–2 |pages=213–27 |year=2012 |pmid=22265413 |doi=10.1016/j.cell.2011.11.031 |s2cid=17832872 |doi-access=free }}
• {{cite journal |vauthors=Zhao J, Jitkaew S, Cai Z, Choksi S, Li Q, Luo J, Liu ZG |title=Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=109 |issue=14 |pages=5322–7 |year=2012 |pmid=22421439 |pmc=3325682 |doi=10.1073/pnas.1200012109 |bibcode=2012PNAS..109.5322Z |doi-access=free }}
• {{cite journal |vauthors=Chen W, Zhou Z, Li L, Zhong CQ, Zheng X, Wu X, Zhang Y, Ma H, Huang D, Li W, Xia Z, Han J |title=Diverse sequence determinants control human and mouse receptor interacting protein 3 (RIP3) and mixed lineage kinase domain-like (MLKL) interaction in necroptotic signaling |journal=J. Biol. Chem. |volume=288 |issue=23 |pages=16247–61 |year=2013 |pmid=23612963 |pmc=3675564 |doi=10.1074/jbc.M112.435545 |doi-access=free }}
• {{cite journal |vauthors=Colbert LE, Fisher SB, Hardy CW, Hall WA, Saka B, Shelton JW, Petrova AV, Warren MD, Pantazides BG, Gandhi K, Kowalski J, Kooby DA, El-Rayes BF, Staley CA, Adsay NV, Curran WJ, Landry JC, Maithel SK, Yu DS |title=Pronecrotic mixed lineage kinase domain-like protein expression is a prognostic biomarker in patients with early-stage resected pancreatic adenocarcinoma |journal=Cancer |volume=119 |issue=17 |pages=3148–55 |year=2013 |pmid=23720157 |pmc=4389890 |doi=10.1002/cncr.28144 }}
• {{cite journal |vauthors=Murphy JM, Lucet IS, Hildebrand JM, Tanzer MC, Young SN, Sharma P, Lessene G, Alexander WS, Babon JJ, Silke J, Czabotar PE |title=Insights into the evolution of divergent nucleotide-binding mechanisms among pseudokinases revealed by crystal structures of human and mouse MLKL |journal=Biochem. J. |volume=457 |issue=3 |pages=369–77 |year=2014 |pmid=24219132 |doi=10.1042/BJ20131270 }}
• {{cite journal |vauthors=Cai Z, Jitkaew S, Zhao J, Chiang HC, Choksi S, Liu J, Ward Y, Wu LG, Liu ZG |title=Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis |journal=Nat. Cell Biol. |volume=16 |issue=1 |pages=55–65 |year=2014 |pmid=24316671 |doi=10.1038/ncb2883 |s2cid=27124722 |pmc=8369836 }}
• {{cite journal |vauthors=Pierdomenico M, Negroni A, Stronati L, Vitali R, Prete E, Bertin J, Gough PJ, Aloi M, Cucchiara S |title=Necroptosis is active in children with inflammatory bowel disease and contributes to heighten intestinal inflammation |journal=Am. J. Gastroenterol. |volume=109 |issue=2 |pages=279–87 |year=2014 |pmid=24322838 |doi=10.1038/ajg.2013.403 |s2cid=25540582 }}
• {{cite journal |vauthors=Wang H, Sun L, Su L, Rizo J, Liu L, Wang LF, Wang FS, Wang X |title=Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3 |journal=Mol. Cell |volume=54 |issue=1 |pages=133–146 |year=2014 |pmid=24703947 |doi=10.1016/j.molcel.2014.03.003 |doi-access=free }}

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