Identifiers
receptor interacting serine/threonine kinase 1
HUGO:RIPK1 hgnc_id:HGNC:10019 HGNC:10019 ENTREZ:8737 UNIPROT:Q13546
receptor (TNFRSF)-interacting serine-threonine kinase 1
HUGO:RIPK1 HGNC:10019 ENTREZ:8737 UNIPROT:Q13546
HUGO:RIPK1

Maps_Modules
HMC:TUMOR_PROMOTING_INFLAMMATION
HMC:ACTIVATING_INVASION_AND_METASTASIS
 Cancer Associated Fibroblasts   / INFLAMMATORY_SIGNALING_PATHWAYS 
HMC:RESISTING_CELL_DEATH
HMC:DEREGULATING_CELLULAR_ENERGETICS
 Regulated Cell Death   / APOPTOSIS 
 Regulated Cell Death   / CASPASES 
 Regulated Cell Death   / DEATH_RECEPTOR_PATHWAYS 
 Regulated Cell Death   / FAS_RESPONSE 
 Regulated Cell Death   / GLUTAMINE_METABOLISM 
 Regulated Cell Death   / NECROPTOSIS 
 Regulated Cell Death   / TNF_RESPONSE 
 Regulated Cell Death   / TRAIL_RESPONSE 
 Regulated Cell Death   / ER_STRESS 
HMC:AVOIDING_IMMUNE_DESTRUCTION
 Innate Immunity   / IMMUNOSTIMULATORY_CYTOKINE_PATHWAYS 
 Innate Immunity   / IMMUNOSTIMULATORY_CORE_PATHWAYS 
HMC:EVADING_GROWTH_SUPPRESSORS
 Survival   / MAPK 

References
PMID:21232017; PMID:18641653
TNF induces TRADD-dependent and RIPK1-dependent recruitment of TRAF2 to TNFR1.
TRADD is essential for TNFR1 signaling in MEFs
PMID:26587781
PMID:19632174
RIP kinases at the crossroads of cell death and survival
PMID:19524513
PMID:28574505
PMID:23010170
PMID:26653790
erastin-induced cell death proceeds normally on knockdown of RIPK1/RIPK3
PMID:21232017, PMID:21133840, PMID:18641653
TNF treatment is thought to result in the formation of a TRADD-RIP-TRAF2 complex at the membrane.
PMID:11274345

Maps_Modules
HMC:RESISTING_CELL_DEATH
HMC:DEREGULATING_CELLULAR_ENERGETICS
 Regulated Cell Death   / APOPTOSIS 
 Regulated Cell Death   / CASPASES 
 Regulated Cell Death   / DEATH_RECEPTOR_PATHWAYS 
 Regulated Cell Death   / FAS_RESPONSE 
 Regulated Cell Death   / GLUTAMINE_METABOLISM 
 Regulated Cell Death   / NECROPTOSIS 
 Regulated Cell Death   / TNF_RESPONSE 
 Regulated Cell Death   / TRAIL_RESPONSE 

References
K48-linked ubiquitin chains
rc_re1333:( Regulated Cell Death  ) PMID:19131965

Maps_Modules
HMC:RESISTING_CELL_DEATH
HMC:DEREGULATING_CELLULAR_ENERGETICS
 Regulated Cell Death   / APOPTOSIS 
 Regulated Cell Death   / CASPASES 
 Regulated Cell Death   / DEATH_RECEPTOR_PATHWAYS 
 Regulated Cell Death   / FAS_RESPONSE 
 Regulated Cell Death   / GLUTAMINE_METABOLISM 
 Regulated Cell Death   / NECROPTOSIS 
 Regulated Cell Death   / TNF_RESPONSE 
 Regulated Cell Death   / TRAIL_RESPONSE 

References
K63-linked ubiquitin chain
rc_re1210( Regulated Cell Death  ):
PMID:18570872
PMID:18621737
PMID:23010170
Complex I-mediated NF-??B stimulation is caused by cIAP-induced
K63-linked polyubiquitination of RIP1 and linear ubiquitin chain
assembly complex (LUBAC)-mediated linear ubiquitination of
RIP1
rc_re1214( Regulated Cell Death  ):
K63-linked polyubiquitination of RIP1 provides a scaffold for the recruitment of TGF-beta-activated kinase 1 (TAK1) binding protein 2 and 3 (TAB2 and 3),
which finally activates TAK1
rc_re1215( Regulated Cell Death  ):
PMID:16603398
rc_re1331( Regulated Cell Death  ):
PMID:19131965
role of RNF11 in the A20 complex
CYLD is required for necroptosis induction by deu-
biquitinating RIP1

Maps_Modules
HMC:RESISTING_CELL_DEATH
HMC:DEREGULATING_CELLULAR_ENERGETICS
 Regulated Cell Death   / APOPTOSIS 
 Regulated Cell Death   / CASPASES 
 Regulated Cell Death   / DEATH_RECEPTOR_PATHWAYS 
 Regulated Cell Death   / FAS_RESPONSE 
 Regulated Cell Death   / GLUTAMINE_METABOLISM 
 Regulated Cell Death   / NECROPTOSIS 
 Regulated Cell Death   / TNF_RESPONSE 
 Regulated Cell Death   / TRAIL_RESPONSE 

References
rc_re1523( Regulated Cell Death  ):
PMID:23010170
RIP3 is known to be phosphotylated by itself
PMID:19524512
The kinase activity of RIP3 is essential for necrosis execution.
rc_re1280( Regulated Cell Death  ):
PMID:17389591
in aortic endothelial cells
rc_re1525( Regulated Cell Death  ):
PMID:19498109
RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis.

Maps_Modules
HMC:RESISTING_CELL_DEATH
HMC:DEREGULATING_CELLULAR_ENERGETICS
 Regulated Cell Death   / APOPTOSIS 
 Regulated Cell Death   / CASPASES 
 Regulated Cell Death   / DEATH_RECEPTOR_PATHWAYS 
 Regulated Cell Death   / FAS_RESPONSE 
 Regulated Cell Death   / GLUTAMINE_METABOLISM 
 Regulated Cell Death   / NECROPTOSIS 
 Regulated Cell Death   / TNF_RESPONSE 
 Regulated Cell Death   / TRAIL_RESPONSE 

References
rc_re1331( Regulated Cell Death  ):
PMID:19131965
role of RNF11 in the A20 complex
PMID:23010170
CYLD is required for necroptosis induction by deu-
biquitinating RIP1
rc_re1210( Regulated Cell Death  ):
PMID:18570872
PMID:18621737
Complex I-mediated NF-??B stimulation is caused by cIAP-induced
K63-linked polyubiquitination of RIP1 and linear ubiquitin chain
assembly complex (LUBAC)-mediated linear ubiquitination of
RIP1
rc_re1234( Regulated Cell Death  ):
PMID:20125124
by HTRA2
PMID:10521396
by CASP8
PMID:19935698
by CASP2
rc_re1334( Regulated Cell Death  ):
TRADD recruits FADD and caspase-8, forming complex IIA, where caspase-8 is activated and apoptosis is initiated
PMID:12887920
rc_re1523( Regulated Cell Death  ):
RIP3 is known to be phosphotylated by itself
PMID:19524512
The kinase activity of RIP3 is essential for necrosis execution.

Maps_Modules
HMC:RESISTING_CELL_DEATH
HMC:DEREGULATING_CELLULAR_ENERGETICS
 Regulated Cell Death   / APOPTOSIS 
 Regulated Cell Death   / CASPASES 
 Regulated Cell Death   / DEATH_RECEPTOR_PATHWAYS 
 Regulated Cell Death   / FAS_RESPONSE 
 Regulated Cell Death   / GLUTAMINE_METABOLISM 
 Regulated Cell Death   / NECROPTOSIS 
 Regulated Cell Death   / TNF_RESPONSE 
 Regulated Cell Death   / TRAIL_RESPONSE 

References
rc_re1149( Regulated Cell Death  ):
PMID:12441346
in murine L929 cell line, RIPK1 is a HSP90 client protein

Maps_Modules
HMC:RESISTING_CELL_DEATH
HMC:DEREGULATING_CELLULAR_ENERGETICS
 Regulated Cell Death   / APOPTOSIS 
 Regulated Cell Death   / CASPASES 
 Regulated Cell Death   / DEATH_RECEPTOR_PATHWAYS 
 Regulated Cell Death   / FAS_RESPONSE 
 Regulated Cell Death   / GLUTAMINE_METABOLISM 
 Regulated Cell Death   / NECROPTOSIS 
 Regulated Cell Death   / TNF_RESPONSE 
 Regulated Cell Death   / TRAIL_RESPONSE 

References
in_re884( Innate Immunity  ):
PMID:14660645, PMID:18264787, PMID:11460167
Activated TAK1 phosphorylates IKK-beta proteins
leading to activation of NF-??B downstream of HMGB1.
PMID:21232017, PMID:21133840, PMID:17301840
PMID:24958845, PMID:24699077
The LUBAC complex ubiquitinates NEMO, a subunit of the IKK complex downstream of TNF and upregulates IkBa degradetion.
PMID:11280761
VEGF signaling blocs TNF-?? induced activation of I??B kinase (IKK complex).This decreased IKK activation correlated with the inhibition of I??B?? phosphorylation and degradation of I??B?? and I??B?? in HPCs, and this inhibition is inhdependent or FLT1 and KDR

References
su_mpk1_mpk1_re123( Survival  ):
TNF treatment is thought to result in the formation of a TRADD-RIP-TRAF2 complex at the membrane.
PMID:11274345

1. RIPK1@Cytoplasm

1. RIPK1@Cytosol
2. RIPK1|​unfolded@Cytosol

1. RIPK1@Endopasmic Reticulum

1. RIPK1@INNATE_IMMUNE_CELL_Cytosol

1. RIPK1@INNATE_IMMUNE_CELL_Membrane

1. RIPK1@TNFRSF1 Receptor Complex
2. RIPK1|​ubi@TNFRSF1 Receptor Complex
3. RIPK1|​K377_ubi@TNFRSF1 Receptor Complex
4. RIPK1|​S161_pho@TNFRSF1 Receptor Complex

1. RIPK1:​TAK1*|​pho:​TNFRSF1A:​TRADD:​TRAF2@Cytoplasm
2. MAP3K1|​pho:​RIPK1:​TNFRSF1A:​TRADD:​TRAF2@Cytoplasm
3. MAP3K5|​pho:​RIPK1:​TNFRSF1A:​TRADD:​TRAF2@Cytoplasm
4. MAP3K2_3*|​pho:​RIPK1:​TNFRSF1A:​TRADD:​TRAF2@Cytoplasm

1. RIPK1|​S161_pho:​RIPK3|​S199_pho@Cytosol
2. FADD:​RIPK1:​TNF:​TNFR1*:​TRADD:​TRAF2@Cytosol
3. FADD:​RIPK1|​ubi:​TNF:​TNFR1*:​TRADD:​TRAF2|​ubi@Cytosol
4. GLUD1:​GLUL:​MLKL|​S358_pho|​T357_pho:​PGAM5|​pho:​PYGL:​RIPK1|​S161_pho:​RIPK3|​S199_pho|​S227_pho@Cytosol

1. IRE1-alpha*:​RIPK1@Endopasmic Reticulum

1. Caspase8,10*|​ubi:​DAXX:​FADD:​FAF1:​FASLG:​FAS|​pal:​FLASH*:​RIPK1@Endosome
2. CFLAR:​Caspase8,10*|​ubi:​FADD:​FAF1:​FASLG:​FAS|​pal:​FLASH*:​MLKL:​RIPK1|​emp|​S161_pho:​RIPK3|​S199_pho@Endosome
3. ASK1*:​CFLAR:​Caspase8,10*|​ubi:​DAXX:​FADD:​FAF1:​FASLG:​FAS|​pal:​FLASH*:​RIPK1|​emp|​K377_ubi:​TRAF2@Endosome

1. FADD:​RIPK1:​TNF:​TNFR1*:​TRADD:​TRAF2@INNATE_IMMUNE_CELL_Membrane
2. FADD:​RIPK1|​ubi:​TNF:​TNFR1*:​TRADD:​TRAF2|​ubi@INNATE_IMMUNE_CELL_Membrane

1. RIPK1:​TNFRSF1A:​TRADD:​TRAF2@Plasma Membrane

1. TNF@default + TNFR1*@Cytosol + TRADD@Cytosol + TRAF2@Cytosol + RIPK1@Cytosol + FADD@Cytosol → FADD:​RIPK1:​TNF:​TNFR1*:​TRADD:​TRAF2@Cytosol
2. FADD:​RIPK1:​TNF:​TNFR1*:​TRADD:​TRAF2@Cytosol → FADD:​RIPK1|​ubi:​TNF:​TNFR1*:​TRADD:​TRAF2|​ubi@Cytosol
3. FADD:​RIPK1:​TNF:​TNFR1*:​TRADD:​TRAF2@INNATE_IMMUNE_CELL_Membrane → FADD:​RIPK1|​ubi:​TNF:​TNFR1*:​TRADD:​TRAF2|​ubi@INNATE_IMMUNE_CELL_Membrane
4. rRIPK1@INNATE_IMMUNE_CELL_Cytosol → RIPK1@INNATE_IMMUNE_CELL_Membrane
5. TNF@default + TNFR1*@INNATE_IMMUNE_CELL_Membrane + TRADD@INNATE_IMMUNE_CELL_Membrane + TRAF2@INNATE_IMMUNE_CELL_Membrane + RIPK1@INNATE_IMMUNE_CELL_Membrane + FADD@INNATE_IMMUNE_CELL_Membrane → FADD:​RIPK1:​TNF:​TNFR1*:​TRADD:​TRAF2@INNATE_IMMUNE_CELL_Membrane
6. RIPK1|​unfolded@Cytosol → RIPK1@Cytosol
7. RIPK1@Cytosol → RIPK1|​unfolded@Cytosol
8. RIPK1@Cytosol → RIPK1@TNFRSF1 Receptor Complex
9. RIPK1@TNFRSF1 Receptor Complex → RIPK1|​K377_ubi@TNFRSF1 Receptor Complex
10. RIPK1@TNFRSF1 Receptor Complex → cleaved~RIPK1*@TNFRSF1 Receptor Complex
11. RIPK1|​K377_ubi@TNFRSF1 Receptor Complex → RIPK1@TNFRSF1 Receptor Complex
12. RIPK1|​ubi@TNFRSF1 Receptor Complex → degraded
13. RIPK1@TNFRSF1 Receptor Complex → RIPK1|​ubi@TNFRSF1 Receptor Complex
14. TRADD@TNFRSF1 Receptor Complex + RIPK1@TNFRSF1 Receptor Complex + FADD@Cytosol → rc_s4026
15. RIPK1@TNFRSF1 Receptor Complex → RIPK1|​S161_pho@TNFRSF1 Receptor Complex
16. RIPK3|​S199_pho@TNFRSF1 Receptor Complex + RIPK1|​S161_pho@TNFRSF1 Receptor Complex + FADD@Cytosol → RIPK1|​S161_pho:​RIPK3|​S199_pho@Cytosol
17. RIPK1|​S161_pho:​RIPK3|​S199_pho@Cytosol + MLKL@Cytosol + GLUL@Cytosol + GLUD1@Cytosol + PYGL@Cytosol + PGAM5@Cytosol → GLUD1:​GLUL:​MLKL|​S358_pho|​T357_pho:​PGAM5|​pho:​PYGL:​RIPK1|​S161_pho:​RIPK3|​S199_pho|​S227_pho@Cytosol
18. GLUD1:​GLUL:​MLKL|​S358_pho|​T357_pho:​PGAM5|​pho:​PYGL:​RIPK1|​S161_pho:​RIPK3|​S199_pho|​S227_pho@Cytosol → Glycogen breakdown@Cytosol
19. GLUD1:​GLUL:​MLKL|​S358_pho|​T357_pho:​PGAM5|​pho:​PYGL:​RIPK1|​S161_pho:​RIPK3|​S199_pho|​S227_pho@Cytosol → Glutaminolysis@Cytosol
20. GLUD1:​GLUL:​MLKL|​S358_pho|​T357_pho:​PGAM5|​pho:​PYGL:​RIPK1|​S161_pho:​RIPK3|​S199_pho|​S227_pho@Cytosol → PARP activation@Cytosol
21. CUL3:​Caspase8,10*|​ubi:​DR4/5*|​gly|​pal:​RBX1@Cytosol + CFLAR@Cytosol + RIPK1@Cytosol + RIPK3@Cytosol + MLKL@Cytosol → CFLAR:​Caspase8,10*|​ubi:​DR4/5*|​gly|​pal:​MLKL:​RIPK3@Cytosol + CUL3:​RBX1@Cytosol
22. Caspase8,10*:​DR4/5*|​gly|​pal@Cytosol + TRAF2@Cytosol + IKBKG@Cytosol + TRADD@Cytosol + RIPK1@Cytosol → Caspase10*:​Caspase8*@Cytosol
23. CFLAR:​Caspase8,10*|​ubi:​DR4/5*|​gly|​pal:​MLKL:​RIPK3@Cytosol → RIPK1|​S161_pho:​RIPK3|​S199_pho@Cytosol
24. FASLG:​FAS|​pal@Cytosol + Caspase8,10*:​FLASH*@Cytosol + FAF1@Cytosol + FADD@Cytosol + DAXX@Cytosol + RIPK1@Cytosol → Caspase8,10*|​ubi:​DAXX:​FADD:​FAF1:​FASLG:​FAS|​pal:​FLASH*:​RIPK1@Endosome
25. Caspase8,10*|​ubi:​DAXX:​FADD:​FAF1:​FASLG:​FAS|​pal:​FLASH*:​RIPK1@Endosome → CFLAR:​Caspase8,10*|​ubi:​FADD:​FAF1:​FASLG:​FAS|​pal:​FLASH*:​MLKL:​RIPK1|​emp|​S161_pho:​RIPK3|​S199_pho@Endosome
26. CFLAR:​Caspase8,10*|​ubi:​FADD:​FAF1:​FASLG:​FAS|​pal:​FLASH*:​MLKL:​RIPK1|​emp|​S161_pho:​RIPK3|​S199_pho@Endosome → ASK1*:​CFLAR:​Caspase8,10*|​ubi:​DAXX:​FADD:​FAF1:​FASLG:​FAS|​pal:​FLASH*:​RIPK1|​emp|​K377_ubi:​TRAF2@Endosome
27. CFLAR:​Caspase8,10*|​ubi:​FADD:​FAF1:​FASLG:​FAS|​pal:​FLASH*:​MLKL:​RIPK1|​emp|​S161_pho:​RIPK3|​S199_pho@Endosome → RIPK1|​S161_pho:​RIPK3|​S199_pho@Cytosol
28. ASK1*:​CFLAR:​Caspase8,10*|​ubi:​DAXX:​FADD:​FAF1:​FASLG:​FAS|​pal:​FLASH*:​RIPK1|​emp|​K377_ubi:​TRAF2@Endosome → ASK1*@Cytosol
29. CFLAR:​Caspase8,10*|​ubi:​FADD:​FAF1:​FASLG:​FAS|​pal:​FLASH*:​MLKL:​RIPK1|​emp|​S161_pho:​RIPK3|​S199_pho@Endosome → Caspase8,10*|​ubi:​DAXX:​FADD:​FAF1:​FASLG:​FAS|​pal:​FLASH*:​RIPK1@Endosome
30. ASK1*:​CFLAR:​Caspase8,10*|​ubi:​DAXX:​FADD:​FAF1:​FASLG:​FAS|​pal:​FLASH*:​RIPK1|​emp|​K377_ubi:​TRAF2@Endosome → CFLAR:​Caspase8,10*|​ubi:​FADD:​FAF1:​FASLG:​FAS|​pal:​FLASH*:​MLKL:​RIPK1|​emp|​S161_pho:​RIPK3|​S199_pho@Endosome
31. ASK1*:​CFLAR:​Caspase8,10*|​ubi:​DAXX:​FADD:​FAF1:​FASLG:​FAS|​pal:​FLASH*:​RIPK1|​emp|​K377_ubi:​TRAF2@Endosome → Caspase8*|​ubi:​FLASH*@Cytosol
32. Caspase8,10*|​ubi:​DAXX:​FADD:​FAF1:​FASLG:​FAS|​pal:​FLASH*:​RIPK1@Endosome → rc_s6308
33. IRE1-alpha*@Endopasmic Reticulum + RIPK1@Endopasmic Reticulum → IRE1-alpha*:​RIPK1@Endopasmic Reticulum
34. RIPK1@Cytoplasm + TNFRSF1A:​TRADD:​TRAF2@Plasma Membrane → RIPK1:​TNFRSF1A:​TRADD:​TRAF2@Plasma Membrane
35. RIPK1:​TNFRSF1A:​TRADD:​TRAF2@Plasma Membrane + TAK1*@Cytoplasm → RIPK1:​TAK1*|​pho:​TNFRSF1A:​TRADD:​TRAF2@Cytoplasm
36. MAP3K1@Cytoplasm + RIPK1:​TNFRSF1A:​TRADD:​TRAF2@Plasma Membrane → MAP3K1|​pho:​RIPK1:​TNFRSF1A:​TRADD:​TRAF2@Cytoplasm
37. MAP3K2_3*@Cytoplasm + RIPK1:​TNFRSF1A:​TRADD:​TRAF2@Plasma Membrane → MAP3K2_3*|​pho:​RIPK1:​TNFRSF1A:​TRADD:​TRAF2@Cytoplasm
38. RIPK1:​TNFRSF1A:​TRADD:​TRAF2@Plasma Membrane + MAP3K5@Cytoplasm → MAP3K5|​pho:​RIPK1:​TNFRSF1A:​TRADD:​TRAF2@Cytoplasm

1. IKBKG:​IKK_alpha_*:​IKK_beta_*@Cytosol → IKBKG|​ubi:​IKK_alpha_*:​IKK_beta_*|​pho@Cytosol
2. MAP3K7@Cytosol + TAB2@Cytosol + TAB3@Cytosol → (MAP3K7:​TAB2:​TAB3)|​active@Cytosol
3. JNK*@Cytosol → JNK*|​pho|​active@Cytosol
4. ERK1/2*@Cytosol → ERK1/2*|​pho@Cytosol
5. MAP3K7@INNATE_IMMUNE_CELL_Cytosol + TAB2@INNATE_IMMUNE_CELL_Cytosol + TAB3@INNATE_IMMUNE_CELL_Cytosol → (MAP3K7:​TAB2:​TAB3)|​active@INNATE_IMMUNE_CELL_Cytosol
6. IKBKG:​IKK_alpha_*:​IKK_beta_*@INNATE_IMMUNE_CELL_Cytosol → IKBKG|​ubi:​IKK_alpha_*:​IKK_beta_*|​pho@INNATE_IMMUNE_CELL_Cytosol
7. JNK*@INNATE_IMMUNE_CELL_Cytosol → JNK*|​pho|​active@INNATE_IMMUNE_CELL_Cytosol
8. p38*@INNATE_IMMUNE_CELL_Cytosol → p38*|​pho|​active@INNATE_IMMUNE_CELL_Cytosol
9. TAB*@Cytosol → TAB*@TNFRSF1 Receptor Complex
10. IKBKG@Cytosol → IKBKG@TNFRSF1 Receptor Complex
11. ATP@Mitochondrial Matrix + ADP@Mitochondrial intermembrane space → ATP@Mitochondrial intermembrane space + ADP@Mitochondrial Matrix
12. DAB2IP@TNFRSF1 Receptor Complex → DAB2IP|​S604_pho@TNFRSF1 Receptor Complex
13. RIPK3@Cytosol → RIPK3@TNFRSF1 Receptor Complex
14. GLUL|​unk@Cytosol → GLUL|​unk|​hm8@Cytosol
15. RIPK1@TNFRSF1 Receptor Complex → RIPK1|​S161_pho@TNFRSF1 Receptor Complex
16. Drp1*|​pho@Cytosol → Drp1*@Cytosol
17. JNK1*@Cytosol → JNK1*|​pho|​active@Cytosol
18. MAP2K4@Cytoplasm → MAP2K4|​pho|​pho@Cytoplasm
19. MAP2K3@Cytoplasm → MAP2K3|​pho|​pho@Cytoplasm
20. MAP2K7@Cytoplasm → MAP2K7|​pho|​pho@Cytoplasm
21. MAP2K6@Cytoplasm → MAP2K6|​pho|​pho@Cytoplasm
22. MEK*@Cytoplasm → MEK*|​pho|​pho@Cytoplasm