Ser345

Site Information
ELSKTQNsIsRtAKS SwissProt Entrez-Gene
Blast this site against: NCBI SwissProt PDB
Site Group ID: 22996309

In vivo Characterization
Methods used to characterize site in vivo:	flow cytometry ( 26 ) , immunoassay ( 2 , 5 , 7 , 10 , 14 , 18 ) , immunoprecipitation ( 18 , 20 , 23 ) , mass spectrometry ( 18 ) , mass spectrometry (in vitro) ( 26 ) , mutation of modification site ( 16 , 23 , 24 , 26 ) , peptide sequencing ( 8 ) , phospho-antibody ( 2 , 3 , 4 , 5 , 6 , 7 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 25 ) , western blotting ( 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 )
Disease tissue studied:	atherosclerosis ( 25 ) , bone cancer ( 11 ) , colorectal cancer ( 3 , 10 , 16 , 22 , 23 , 24 ) , colorectal carcinoma ( 3 , 10 , 16 , 23 , 24 ) , lymphoma ( 16 , 24 ) , fibrosarcoma of soft tissue ( 3 , 8 , 12 , 16 , 23 )
Relevant cell line - cell type - tissue:	'brain, cerebral cortex' ( 14 ) , 'heart, ventricle' ( 9 ) , 3T3 (fibroblast) ( 16 , 23 ) , aorta ( 25 ) , ARPE19 (retinal) ( 5 ) , ATRFLOX (intestinal) ( 3 ) , COLO-205 (intestinal) ( 3 ) , colon ( 7 ) , CT26 (epithelial) ( 22 ) , fibroblast ( 2 ) , fibroblast-embryo ( 23 ) , fibroblast-skin ( 4 , 16 , 24 , 26 ) , HCT116 (intestinal) ( 3 ) , HCT15 (intestinal) ( 3 ) , HCT8 (intestinal) ( 3 ) , HEK293T (epithelial) ( 10 ) , HeLa (cervical) ( 23 ) , HT-29 (intestinal) ( 10 , 16 , 23 , 24 ) , L929 (fibroblast) ( 3 , 8 , 12 , 16 , 23 ) , LoVo (intestinal) ( 3 ) , Ls174T (intestinal) ( 3 ) , macrophage-bone marrow ( 4 , 11 , 13 , 17 , 18 , 19 ) , MEF (fibroblast) ( 8 , 10 , 12 , 18 , 20 , 21 ) , microvessel endothelial-lung ( 15 ) , myocyte-heart ( 6 , 9 ) , neuron-brain ( 14 ) , retina ( 5 ) , RKO (intestinal) ( 3 ) , SVEC (endothelial) ( 23 ) , SW-1417 (intestinal) ( 3 ) , SW-948 (intestinal) ( 3 ) , SW480 (intestinal) ( 3 ) , SW620 (intestinal) ( 3 ) , testis ( 10 ) , U-937 (myeloid) ( 16 , 24 ) , WiDr (epithelial) ( 3 )

Upstream Regulation
Regulatory protein:	ABCA1 (human) ( 5 ) , ATR (human) ( 5 ) , CASP8 (human) ( 4 ) , CK1G2 (mouse) ( 10 ) , FADD (mouse) ( 22 ) , FAM105B (human) ( 18 ) , IFNB1 (mouse) ( 19 ) , MAPKAPK2 (mouse) ( 13 ) , MYD88 (mouse) ( 13 ) , NHE1 (human) ( 3 ) , OASL (human) ( 2 ) , RDH8 (human) ( 5 ) , RIPK1 (human) ( 3 ) , RIPK1 (mouse) ( 14 ) , RIPK3 (human) ( 3 , 8 ) , RIPK3 (mouse) ( 10 , 14 , 22 ) , SPATA2 (mouse) ( 21 ) , STING (mouse) ( 19 ) , TICAM1 (mouse) ( 13 ) , TTP (mouse) ( 13 ) , ULK1 (human) ( 12 )
Putative in vivo kinases:	RIPK3 (human) ( 3 , 10 , 23 )
Kinases, in vitro:	RIPK3 (mouse) ( 26 )
Treatments:	1,6-Hexanediol ( 2 ) , all-trans-retinal dimer ( 5 ) , amiloride ( 3 ) , cariporide ( 3 ) , circRNA ( 6 ) , cycloheximide ( 4 ) , development ( 10 ) , digitonin ( 3 ) , EP4-D ( 7 ) , GSK'872 ( 5 , 8 , 23 ) , GW440139B ( 23 ) , hypertonic_buffer ( 3 ) , hypotonic_buffer ( 3 ) , hypoxia/reoxygenation ( 6 ) , ischemia/reperfusion ( 14 ) , isoproterenol ( 9 ) , low_pH ( 3 ) , LPS ( 4 , 10 , 11 , 13 , 19 ) , LY2228820 ( 13 ) , N-retinilidene-N- retinyl ethanolamine ( 5 ) , Necrostatin-1 ( 3 , 5 , 9 , 15 ) , Necrostatin7 ( 5 ) , phenhydan ( 16 ) , Q-VD-OPh ( 8 ) , SM-164 ( 20 ) , smac ( 4 ) , sucrose ( 3 ) , TNF ( 4 , 8 , 10 , 12 , 13 , 15 , 16 , 18 , 20 , 23 ) , TRAIL ( 10 ) , virus infection ( 2 ) , Z-IETD-fmk ( 13 ) , Z-VAD-FMK ( 3 , 4 , 7 , 10 , 11 , 12 , 13 , 16 , 17 , 18 , 19 , 20 , 23 )

Downstream Regulation
Effects of modification on MLKL:	activity, induced ( 23 ) , intracellular localization ( 5 , 7 , 23 ) , molecular association, regulation ( 5 ) , protein conformation ( 23 )
Effects of modification on biological processes:	apoptosis, induced ( 11 , 15 , 16 ) , signaling pathway regulation ( 13 )
Induce interaction with:	MLKL (human) ( 5 )

References
1	Sun Z, et al. (2023) β1 integrin signaling governs necroptosis via the chromatin-remodeling factor CHD4. Cell Rep 42, 113322 37883227 Curated Info
2	Lee SA, et al. (2023) OASL phase condensation induces amyloid-like fibrillation of RIPK3 to promote virus-induced necroptosis. Nat Cell Biol 25, 92-107 36604592 Curated Info
3	Zhang W, Fan W, Guo J, Wang X (2022) Osmotic stress activates RIPK3/MLKL-mediated necroptosis by increasing cytosolic pH through a plasma membrane Na/H exchanger. Sci Signal 15, eabn5881 35580168 Curated Info
4	Li X, et al. (2022) Caspase-8 auto-cleavage regulates programmed cell death and collaborates with RIPK3/MLKL to prevent lymphopenia. Cell Death Differ 35064213 Curated Info
5	Pan C, et al. (2021) Lipofuscin causes atypical necroptosis through lysosomal membrane permeabilization. Proc Natl Acad Sci U S A 118 34782457 Curated Info
6	Gao XQ, et al. (2021) The circRNA CNEACR regulates necroptosis of cardiomyocytes through Foxa2 suppression. Cell Death Differ 34588633 Curated Info
7	Patankar JV, et al. (2021) E-type prostanoid receptor 4 drives resolution of intestinal inflammation by blocking epithelial necroptosis. Nat Cell Biol 23, 796-807 34239062 Curated Info
8	Wu W, et al. (2021) TNF-induced necroptosis initiates early autophagy events via RIPK3-dependent AMPK activation, but inhibits late autophagy. Autophagy, 1-18 33779513 Curated Info
9	Wu P, Cai M, Liu J, Wang X (2021) Catecholamine Surges Cause Cardiomyocyte Necroptosis a RIPK1-RIPK3-Dependent Pathway in Mice. Front Cardiovasc Med 8, 740839 34604361 Curated Info
10	Li D, et al. (2020) Casein kinase 1G2 suppresses necroptosis-promoted testis aging by inhibiting receptor-interacting kinase 3. Elife 9 33206046 Curated Info
11	Hao Q, et al. (2020) Enhanced RIPK3 kinase activity-dependent lytic cell death in M1 but not M2 macrophages. Mol Immunol 33221042 Curated Info
12	Wu W, et al. (2020) The Autophagy-Initiating Kinase ULK1 Controls RIPK1-Mediated Cell Death. Cell Rep 31, 107547 32320653 Curated Info
13	Ariana A, et al. (2020) Tristetraprolin regulates necroptosis during tonic Toll-like receptor 4 (TLR4) signaling in murine macrophages. J Biol Chem 32094226 Curated Info
14	Naito MG, et al. (2020) Sequential activation of necroptosis and apoptosis cooperates to mediate vascular and neural pathology in stroke. Proc Natl Acad Sci U S A 117 32071228 Curated Info
15	Fritsch M, et al. (2019) Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis. Nature 575, 683-687 31748744 Curated Info
16	Moerke C, et al. (2018) The anticonvulsive Phenhydan suppresses extrinsic cell death. Cell Death Differ 30442947 Curated Info
17	Sarhan J, et al. (2018) Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during infection. Proc Natl Acad Sci U S A 115, E10888-E10897 30381458 Curated Info
18	Heger K, et al. (2018) OTULIN limits cell death and inflammation by deubiquitinating LUBAC. Nature 559, 120-124 29950720 Curated Info
19	Sarhan J, et al. (2018) Constitutive interferon signaling maintains critical threshold of MLKL expression to license necroptosis. Cell Death Differ 29786074 Curated Info
20	Wang H, et al. (2017) PELI1 functions as a dual modulator of necroptosis and apoptosis by regulating ubiquitination of RIPK1 and mRNA levels of c-FLIP. Proc Natl Acad Sci U S A 114, 11944-11949 29078411 Curated Info
21	Wei R, et al. (2017) SPATA2 regulates the activation of RIPK1 by modulating linear ubiquitination. Genes Dev 31, 1162-1176 28701375 Curated Info
22	Aaes TL, et al. (2016) Vaccination with Necroptotic Cancer Cells Induces Efficient Anti-tumor Immunity. Cell Rep 15, 274-87 27050509 Curated Info
23	Rodriguez DA, et al. (2016) Characterization of RIPK3-mediated phosphorylation of the activation loop of MLKL during necroptosis. Cell Death Differ 23, 76-88 26024392 Curated Info
24	Tanzer MC, et al. (2015) Necroptosis signalling is tuned by phosphorylation of MLKL residues outside the pseudokinase domain activation loop. Biochem J 471, 255-65 26283547 Curated Info
25	Meng L, Jin W, Wang X (2015) RIP3-mediated necrotic cell death accelerates systematic inflammation and mortality. Proc Natl Acad Sci U S A 112, 11007-12 26283397 Curated Info
26	Murphy JM, et al. (2013) The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. Immunity 39, 443-53 24012422 Curated Info