Receptor-interacting serine/threonine-protein kinase 1

Function

Serine-threonine kinase which is a key regulator of TNF-mediated apoptosis, necroptosis and inflammatory pathways. Exhibits kinase activity-dependent functions that regulate cell death and kinase-independent scaffold functions regulating inflammatory signaling and cell survival. Has kinase-independent scaffold functions: upon binding of TNF to TNFR1, RIPK1 is recruited to the TNF-R1 signaling complex (TNF-RSC also known as complex I) where it acts as a scaffold protein promoting cell survival, in part, by activating the canonical NF-kappa-B pathway (By similarity). Kinase activity is essential to regulate necroptosis and apoptosis, two parallel forms of cell death: upon activation of its protein kinase activity, regulates assembly of two death-inducing complexes, namely complex IIa (RIPK1-FADD-CASP8), which drives apoptosis, and the complex IIb (RIPK1-RIPK3-MLKL), which drives necroptosis (By similarity). RIPK1 is required to limit CASP8-dependent TNFR1-induced apoptosis (By similarity). In normal conditions, RIPK1 acts as an inhibitor of RIPK3-dependent necroptosis, a process mediated by RIPK3 component of complex IIb, which catalyzes phosphorylation of MLKL upon induction by ZBP1. Inhibits RIPK3-mediated necroptosis via FADD-mediated recruitment of CASP8, which cleaves RIPK1 and limits TNF-induced necroptosis. Required to inhibit apoptosis and necroptosis during embryonic development: acts by preventing the interaction of TRADD with FADD thereby limiting aberrant activation of CASP8 (By similarity). In addition to apoptosis and necroptosis, also involved in inflammatory response by promoting transcriptional production of pro-inflammatory cytokines, such as interleukin-6 (IL6). Phosphorylates RIPK3: RIPK1 and RIPK3 undergo reciprocal auto- and trans-phosphorylation. Phosphorylates DAB2IP at 'Ser-728' in a TNF-dependent manner, and thereby activates the MAP3K5-JNK apoptotic cascade. Required for ZBP1-induced NF-kappa-B activation in response to DNA damage (By similarity).

Classification

Family (Pfam)

PF00531 Death, PF07714 PK_Tyr_Ser-Thr

InterPro

DEATH-like_dom_sf, Death_dom, Kinase-like_dom_sf, Prot_kinase_dom, RIP1_Death, Ser-Thr/Tyr_kinase_cat_dom, Ser/Thr_kinase_AS, Ser/Thr_Kinases-Pseudokinases

Functional cluster

Phosphoribosyltransferases & related

Experimental structures · PDB · 28

• 4ITH X-ray 2.25A
• 4ITI X-ray 2.86A
• 4ITJ X-ray 1.80A
• 4NEU X-ray 2.57A
• 5HX6 X-ray 2.23A
• 5TX5 X-ray 2.56A
• 5V7Z NMR
• 6AC5 X-ray 1.45A
• 6C3E X-ray 2.60A
• 6C4D X-ray 2.52A
• 6HHO X-ray 3.49A
• 6NW2 X-ray 2.00A
• … and 16 more

A predicted model is available from AlphaFold.

Gene Ontology · 69

• GO:0005737 cytoplasm
• GO:0005829 cytosol
• GO:0031264 death-inducing signaling complex
• GO:0010008 endosome membrane
• GO:0005739 mitochondrion
• GO:0005886 plasma membrane
• GO:0032991 protein-containing complex
• GO:0043235 receptor complex
• GO:0097342 ripoptosome
• GO:0005524 ATP binding
• GO:0070513 death domain binding
• GO:0005123 death receptor binding
• GO:0042802 identical protein binding
• GO:0004706 JUN kinase kinase kinase activity
• GO:0042803 protein homodimerization activity
• GO:0004672 protein kinase activity
• GO:0106310 protein serine kinase activity
• GO:0004674 protein serine/threonine kinase activity
• GO:0120283 protein serine/threonine kinase binding
• GO:0004722 protein serine/threonine phosphatase activity
• GO:0044877 protein-containing complex binding
• GO:0035591 signaling adaptor activity
• GO:0031625 ubiquitin protein ligase binding
• GO:0032147 activation of protein kinase activity
• GO:1990000 amyloid fibril formation
• GO:0006915 apoptotic process
• GO:0007249 canonical NF-kappaB signal transduction
• GO:0071363 cellular response to growth factor stimulus
• GO:0070301 cellular response to hydrogen peroxide
• GO:0071356 cellular response to tumor necrosis factor
• GO:0097191 extrinsic apoptotic signaling pathway
• GO:0008625 extrinsic apoptotic signaling pathway via death domain receptors
• GO:0006954 inflammatory response
• GO:0035556 intracellular signal transduction
• GO:0008630 intrinsic apoptotic signaling pathway in response to DNA damage
• GO:0070266 necroptotic process
• GO:0097527 necroptotic signaling pathway
• GO:0043066 negative regulation of apoptotic process
• GO:0043124 negative regulation of canonical NF-kappaB signal transduction
• GO:2001237 negative regulation of extrinsic apoptotic signaling pathway
• GO:2001240 negative regulation of extrinsic apoptotic signaling pathway in absence of ligand
• GO:0060546 negative regulation of necroptotic process
• GO:0043065 positive regulation of apoptotic process
• GO:0043123 positive regulation of canonical NF-kappaB signal transduction
• GO:1900119 positive regulation of execution phase of apoptosis
• GO:2001238 positive regulation of extrinsic apoptotic signaling pathway
• GO:0010628 positive regulation of gene expression
• GO:0050729 positive regulation of inflammatory response
• GO:0070105 positive regulation of interleukin-6-mediated signaling pathway
• GO:0032757 positive regulation of interleukin-8 production
• GO:0046330 positive regulation of JNK cascade
• GO:0045651 positive regulation of macrophage differentiation
• GO:1903800 positive regulation of miRNA processing
• GO:0060545 positive regulation of necroptotic process
• GO:0043525 positive regulation of neuron apoptotic process
• GO:1901224 positive regulation of non-canonical NF-kappaB signal transduction
• GO:0043068 positive regulation of programmed cell death
• GO:0062100 positive regulation of programmed necrotic cell death
• GO:2000379 positive regulation of reactive oxygen species metabolic process
• GO:0045944 positive regulation of transcription by RNA polymerase II
• GO:0032760 positive regulation of tumor necrosis factor production
• GO:1903265 positive regulation of tumor necrosis factor-mediated signaling pathway
• GO:0097300 programmed necrotic cell death
• GO:0006979 response to oxidative stress
• GO:0034612 response to tumor necrosis factor
• GO:0097343 ripoptosome assembly
• GO:1901026 ripoptosome assembly involved in necroptotic process
• GO:0070231 T cell apoptotic process
• GO:0033209 tumor necrosis factor-mediated signaling pathway

Disease associations

• immunodeficiency 57 MONDO:0020849
• autoinflammation with episodic fever and lymphadenopathy MONDO:0030018

Drugs targeting this protein · 1

• GSK2982772 inhibitor

Related proteins · sequence + function similarity

• Receptor-interacting serine/threonine-protein kinase 1 0.98
• Receptor-interacting serine/threonine-protein kinase 2 0.73
• Receptor-interacting serine/threonine-protein kinase 2 0.69
• Receptor-interacting serine/threonine-protein kinase 2 0.67
• Mitogen-activated protein kinase kinase kinase 20 0.64
• Mitogen-activated protein kinase kinase kinase 20 0.63
• Interleukin-1 receptor-associated kinase 3 0.61
• Interleukin-1 receptor-associated kinase 3 0.60
• Lymphokine-activated killer T-cell-originated protein kinase 0.56
• Interleukin-1 receptor-associated kinase 4 0.55
• Serine/threonine-protein kinase Nek11 0.54
• Lymphokine-activated killer T-cell-originated protein kinase 0.54

Co-cited proteins · studied together in the literature

• Receptor-interacting serine/threonine-protein kinase 3 12 shared papers
• Receptor-interacting serine/threonine-protein kinase 1 10 shared papers
• Tumor necrosis factor receptor type 1-associated DEATH domain protein 6 shared papers
• E3 ubiquitin-protein ligase rififylin 1 shared papers
• E3 ubiquitin-protein ligase RNF216 1 shared papers
• Effector protease OspD3 1 shared papers
• Caspase-8 4 shared papers
• Tumor necrosis factor alpha-induced protein 3 1 shared papers
• Zinc finger protein RFP 1 shared papers
• FAS-associated death domain protein 4 shared papers
• Small hydrophobic protein 1 shared papers
• Tumor necrosis factor receptor superfamily member 1A 5 shared papers

Literature · 61 cited papers

• Grb2 interacts with necrosome components and is involved in rasfonin-induced necroptosis. Cell. Death. Discov. · 2022
• A unique bacterial tactic to circumvent the cell death crosstalk induced by blockade of caspase-8. EMBO J. · 2020
• Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease. Nature · 2020
• A dominant autoinflammatory disease caused by non-cleavable variants of RIPK1. Nature · 2020
• Ripoptocide - A Spark for Inflammation. Front. Cell Dev. Biol. · 2019
• Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation. Nat. Commun. · 2019
• Structural and functional insights into host death domains inactivation by the bacterial arginine GlcNAcyltransferase effector. Mol. Cell · 2019
• Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation. Science · 2018
• PELI1 selectively targets kinase-active RIP3 for ubiquitylation-dependent proteasomal degradation. Mol. Cell · 2018
• The structure of the necrosome RIPK1-RIPK3 core, a human hetero-amyloid signaling complex. Cell · 2018
• Death-domain dimerization-mediated activation of RIPK1 controls necroptosis and RIPK1-dependent apoptosis. Proc. Natl. Acad. Sci. U.S.A. · 2018
• Mumps virus SH protein inhibits NF-kappaB activation by interacting with tumor necrosis factor receptor 1, interleukin-1 receptor 1, and Toll-like receptor 3 complexes. J. Virol. · 2017
• … and 49 more in the literature graph