receptor interacting serine/threonine kinase 3 | Receptor interacting protein kinase (RIPK) family | IUPHAR Guide to IMMUNOPHARMACOLOGY

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receptor interacting serine/threonine kinase 3

  Target has curated data in GtoImmuPdb

Target id: 2191

Nomenclature: receptor interacting serine/threonine kinase 3

Abbreviated Name: RIPK3

Family: Receptor interacting protein kinase (RIPK) family

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 518 14q12 RIPK3 receptor interacting serine/threonine kinase 3
Mouse - 486 14 C1 Ripk3 receptor-interacting serine-threonine kinase 3
Rat - 478 15 p13 Ripk3 receptor-interacting serine-threonine kinase 3
Previous and Unofficial Names
RIP3 | homocysteine respondent protein HCYP2 | RIP-like protein kinase 3
Database Links
BRENDA
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Enzyme Reaction
EC Number: 2.7.11.1

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Parameter Reference
RIPK1 inhibitor 22b Hs Inhibition 5.1 pKd 5
pKd 5.1 (Kd 7.2x10-6 M) [5]
ponatinib Hs Inhibition 8.8 pKi 8
pKi 8.8 (Ki 1.6x10-9 M) [8]
Description: Inhibition of recombinant RIPK3 in an in vitro ADP-Glo assay (Promega).
Immunopharmacology Comments
RIPK1 and RIPK3 are involved in necroptosis and as such are critical regulators of inflammation and cell death [9-12]. RIPK-targeting necroptosis inhibitors are being developed to target inflammation mediated disorders [4], including the development of novel therapeutics for the treatment of TNF-induced systemic inflammatory response syndrome (SIRS) and sepsis, as well as cancer [7,13].
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 1 GO processes
GO:2000452 regulation of CD8-positive, alpha-beta cytotoxic T cell extravasation ISS
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 5 GO processes
GO:0001914 regulation of T cell mediated cytotoxicity ISS
GO:0002819 regulation of adaptive immune response ISS
GO:0033077 T cell differentiation in thymus ISS
GO:0046006 regulation of activated T cell proliferation ISS
GO:0070235 regulation of activation-induced cell death of T cells ISS
Immuno Process:  B cell (activation)
GO Annotations:  Associated to 2 GO processes
GO:0001914 regulation of T cell mediated cytotoxicity ISS
GO:0002819 regulation of adaptive immune response ISS
Immuno Process:  Immune regulation
GO Annotations:  Associated to 6 GO processes
GO:0001914 regulation of T cell mediated cytotoxicity ISS
GO:0002819 regulation of adaptive immune response ISS
GO:0043029 T cell homeostasis ISS
GO:0046006 regulation of activated T cell proliferation ISS
GO:0070235 regulation of activation-induced cell death of T cells ISS
GO:2000452 regulation of CD8-positive, alpha-beta cytotoxic T cell extravasation ISS
Immuno Process:  Immune system development
GO Annotations:  Associated to 4 GO processes
GO:0033077 T cell differentiation in thymus ISS
GO:0048535 lymph node development ISS
GO:0048536 spleen development ISS
GO:0048538 thymus development ISS
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 1 GO processes
GO:0032649 regulation of interferon-gamma production ISS
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 2 GO processes
GO:0046006 regulation of activated T cell proliferation ISS
GO:2000452 regulation of CD8-positive, alpha-beta cytotoxic T cell extravasation ISS
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 2 GO processes
GO:0033077 T cell differentiation in thymus ISS
GO:0046006 regulation of activated T cell proliferation ISS
Physiological Functions
RIPK3 is an essential regulator of TNF-induced necrosis.
Species:  Mouse
Tissue: 
References:  1,3,14
Physiological Consequences of Altering Gene Expression
RIPK3 knockout mice are devoid of inflammation inflicted tissue damage in an acute pancreatitis model, and exhibit severely impaired virus-induced tissue necrosis, inflammation, and control of viral replication.
Species:  Mouse
Tissue: 
Technique:  Gene knockout.
References:  1,3
Deletion of RIPK3 confers complete protection against lethal TNF-induced systemic inflammatory response syndrome (SIRS).
Species:  Mouse
Tissue: 
Technique:  Gene knockout.
References:  2
General Comments
The role of RIPK3 as a critical regulator of programmed necrosis (necroptosis) is reviewed in [6].

References

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1. Cho YS, Challa S, Moquin D, Genga R, Ray TD, Guildford M, Chan FK. (2009) Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell, 137 (6): 1112-23. [PMID:19524513]

2. Duprez L, Takahashi N, Van Hauwermeiren F, Vandendriessche B, Goossens V, Vanden Berghe T, Declercq W, Libert C, Cauwels A, Vandenabeele P. (2011) RIP kinase-dependent necrosis drives lethal systemic inflammatory response syndrome. Immunity, 35 (6): 908-18. [PMID:22195746]

3. He S, Wang L, Miao L, Wang T, Du F, Zhao L, Wang X. (2009) Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell, 137 (6): 1100-11. [PMID:19524512]

4. Kopalli SR, Kang TB, Koppula S. (2016) Necroptosis inhibitors as therapeutic targets in inflammation mediated disorders - a review of the current literature and patents. Expert Opin Ther Pat, 26 (11): 1239-1256. [PMID:27568917]

5. Li Y, Xiong Y, Zhang G, Zhang L, Yang W, Yang J, Huang LY, Qiao Z, Miao Z, Lin G et al.. (2018) Identification of 5-(2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine Derivatives as a New Class of Receptor-Interacting Protein Kinase 1 (RIPK1) Inhibitors, Which Showed Potent Activity in a Tumor Metastasis Model. J. Med. Chem., [Epub ahead of print]. [PMID:30480444]

6. Moriwaki K, Chan FK. (2013) RIP3: a molecular switch for necrosis and inflammation. Genes Dev., 27 (15): 1640-9. [PMID:23913919]

7. Najafov A, Chen H, Yuan J. (2017) Necroptosis and Cancer. Trends Cancer, 3 (4): 294-301. [PMID:28451648]

8. Najjar M, Suebsuwong C, Ray SS, Thapa RJ, Maki JL, Nogusa S, Shah S, Saleh D, Gough PJ, Bertin J et al.. (2015) Structure guided design of potent and selective ponatinib-based hybrid inhibitors for RIPK1. Cell Rep, 10 (11): 1850-60. [PMID:25801024]

9. Newton K. (2015) RIPK1 and RIPK3: critical regulators of inflammation and cell death. Trends Cell Biol., 25 (6): 347-53. [PMID:25662614]

10. Rickard JA, O'Donnell JA, Evans JM, Lalaoui N, Poh AR, Rogers T, Vince JE, Lawlor KE, Ninnis RL, Anderton H et al.. (2014) RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis. Cell, 157 (5): 1175-88. [PMID:24813849]

11. Silke J, Rickard JA, Gerlic M. (2015) The diverse role of RIP kinases in necroptosis and inflammation. Nat. Immunol., 16 (7): 689-97. [PMID:26086143]

12. Vince JE, Silke J. (2016) The intersection of cell death and inflammasome activation. Cell. Mol. Life Sci., 73 (11-12): 2349-67. [PMID:27066895]

13. Wang T, Jin Y, Yang W, Zhang L, Jin X, Liu X, He Y, Li X. (2017) Necroptosis in cancer: An angel or a demon?. Tumour Biol., 39 (6): 1010428317711539. [PMID:28651499]

14. Zhang DW, Shao J, Lin J, Zhang N, Lu BJ, Lin SC, Dong MQ, Han J. (2009) RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science, 325 (5938): 332-6. [PMID:19498109]

How to cite this page

Receptor interacting protein kinase (RIPK) family: receptor interacting serine/threonine kinase 3. Last modified on 11/12/2018. Accessed on 18/02/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2191.