Nomenclature
Short Name:
RIPK1
Full Name:
Receptor-interacting serine-threonine-protein kinase 2
Alias:
- EC 2.7.11.1
- RIK1
- RIP
Classification
Type:
Protein-serine/threonine kinase
Group:
TKL
Family:
RIPK
SubFamily:
NA
Specific Links
Structure
Mol. Mass (Da):
75,931
# Amino Acids:
671
# mRNA Isoforms:
2
mRNA Isoforms:
75,931 Da (671 AA; Q13546); 70,733 Da (625 AA; Q13546-2)
4D Structure:
Binds to the death domain of TNFRSF6 and TRADD. Is recruited by TRADD to TNFRSF1A in a TNF-dependent process. Binds RIPK3, UBCE7IP1 isoform 3 (ZIN), EGFR, IKBKG, TRAF1, TRAF2 and TRAF3. Interacts with BNLF1. Interacts with SQSTM1 upon TNF-alpha stimulation. May interact with MAVS/IPS1. Interacts with ZFAND5. Interacts with RBCK1
1D Structure:
3D Image (rendered using PV Viewer):
PDB ID
Subfamily Alignment
Domain Distribution:
| Start | End | Domain |
|---|---|---|
| 17 | 289 | Pkinase |
| 290 | 321 | Coiled-coil |
| 583 | 669 | DEATH |
Kinexus Products
Click on entries below for direct links to relevant products from Kinexus for this protein kinase.
hiddentext
Post-translation Modifications
For detailed information on phosphorylation of this kinase go to PhosphoNET
Acetylated:
K530, K642, K648.
Serine phosphorylated:
S6, S14, S15, S20, S25, S32, S161+, S166+, S303, S320, S330, S331, S333, S389, S416, S470, S471.
Threonine phosphorylated:
T38, T483.
Tyrosine phosphorylated:
Y384, Y387, Y426, Y463, Y469, Y490+.
Ubiquitinated:
K115, K184, K316, K377, K571, K604, K627.
Distribution
Based on gene microarray analysis from the NCBI
Human Tissue Distribution
% Max Expression:
Mean Expression:
Number of Samples:
Standard Deviation:
% Max Expression:
Mean Expression:
Number of Samples:
Standard Deviation:
22
1472
19
1185
0.5
36
12
26
2
158
10
161
9
582
86
1456
12
830
24
642
0.7
46
46
16
6
380
33
533
17
1111
36
2882
7
498
10
482
2
120
91
129
2
130
27
176
8
554
134
663
2
116
21
108
0.6
38
11
29
2
122
16
226
0.8
52
14
15
5
357
264
2212
1.2
81
18
96
1.3
86
76
66
11
719
84
616
2
109
24
161
3
189
27
350
2
143
19
183
0.6
38
18
50
3
172
25
289
8
552
59
667
1.4
94
24
103
3
224
19
639
1.3
89
19
118
5
334
28
386
18
1179
18
767
100
6687
32
10981
1
70
65
143
13
886
57
765
1.3
89
35
70
Evolution
Species Conservation
PhosphoNET % Identity:
PhosphoNET % Similarity:
Homologene %
Identity:
PhosphoNET % Identity:
PhosphoNET % Similarity:
Homologene %
Identity:
100
100
100
79.3
79.7
99
94.2
96.7
94
-
-
75
-
-
-
63.9
70.4
79
-
-
-
70.2
81.1
72
70.8
80.8
72
-
-
-
42.6
53
-
49
66
52
43.8
60.5
49
39.3
58
43
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
For a wider analysis go to PhosphoNET Evolution in PhosphoNET
Binding Proteins
Examples of known interacting proteins
hiddentext
| No. | Name – UniProt ID |
|---|---|
| 1 | TNFRSF1A - P19438 |
| 2 | FADD - Q13158 |
| 3 | TNFAIP3 - P21580 |
| 4 | CRADD - P78560 |
| 5 | CFLAR - O15519 |
| 6 | TAX1BP1 - Q86VP1 |
| 7 | RNF11 - Q9Y3C5 |
| 8 | TRPC4AP - Q8TEL6 |
| 9 | TICAM1 - Q8IUC6 |
| 10 | RIPK3 - Q9Y572 |
| 11 | EGFR - P00533 |
| 12 | CASP10 - Q92851 |
| 13 | HSPA8 - P11142 |
Regulation
Activation:
NA
Inhibition:
NA
Synthesis:
NA
Degradation:
NA
Known Upstream Kinases
For further details on these substrates click on the Substrate Short Name or UniProt ID. Phosphosite Location is hyperlinked to PhosphoNET
predictions.
Based on in vitro and/or in vivo phosphorylation data
| Kinase Short Name | UniProt ID (Human) | Phosphosite Location | Phosphosite Sequence | Effect of Phosphorylation |
|---|
Known Downstream Substrates
For further details on these substrates click on the Substrate Short Name or UniProt ID. Phosphosite Location is hyperlinked to PhosphoNET
predictions.
Based on in vitro and/or in vivo phosphorylation data
| Substrate Short Name | UniProt ID (Human) | Phosphosite Location | Phosphosite Sequence | Effect of Phosphorylation |
|---|
Protein Kinase Specificity
Matrix of observed frequency (%) of amino acids in aligned protein substrate phosphosites
Matrix Type:
Predicted from the application of the Kinexus Kinase Substrate Predictor Version 2.0 algorithm, which was trained with over 10,000 kinase-protein substrate pairs and 8,000 kinase-peptide substrate pairs.
Domain #:
1
Inhibitors
For further details on these inhibitors click on the Compound Name and enter it into DrugKiNET or click on the ID's
Based on in vitro and/or in vivo phosphorylation data
| Compound Name | KD, Ki or IC50 (nM) | PubChem ID | ChEMBL ID | PubMed ID |
|---|
| Tozasertib | Kd = 20 nM | 5494449 | 572878 | 18183025 |
| KW2449 | Kd = 64 nM | 11427553 | 1908397 | 22037378 |
| AST-487 | Kd = 210 nM | 11409972 | 574738 | 18183025 |
| Nintedanib | Kd = 240 nM | 9809715 | 502835 | 22037378 |
| Pazopanib | Kd = 260 nM | 10113978 | 477772 | 18183025 |
| Dovitinib | Kd = 320 nM | 57336746 | 18183025 | |
| Sunitinib | Kd = 370 nM | 5329102 | 535 | 18183025 |
| Foretinib | Kd = 850 nM | 42642645 | 1230609 | 22037378 |
| Quizartinib | Kd = 890 nM | 24889392 | 576982 | 22037378 |
| Aurora A Inhibitor 23 (DF) | Kd = 1 µM | 21992004 | ||
| WZ3146 | Kd > 1 µM | 44607360 | 20033049 | |
| WZ4002 | Kd > 1 µM | 44607530 | 20033049 | |
| Lestaurtinib | Kd = 1.2 µM | 126565 | 18183025 | |
| SU14813 | Kd = 1.2 µM | 10138259 | 1721885 | 18183025 |
| PHA-665752 | Kd = 1.5 µM | 10461815 | 450786 | 22037378 |
| Crizotinib | Kd = 1.6 µM | 11626560 | 601719 | 22037378 |
| JNJ-7706621 | Kd = 1.8 µM | 5330790 | 191003 | 18183025 |
| Axitinib | Kd = 2.5 µM | 6450551 | 1289926 | 22037378 |
| Linifanib | Kd = 2.8 µM | 11485656 | 223360 | 18183025 |
Disease Linkage
General Disease Association:
Cognitive impairment
Specific Diseases (Non-cancerous):
Mental retardation, autosomal recessive 34 (MRT34)
Comments:
Mental retardation, autosomal recessive 34 (MRT34) is a condition characterized by cognitive impairment, rudimentary speech, and with disease onset during the development period.
Gene Expression in Cancers:
TranscriptoNET (www.transcriptonet.ca) analysis with mRNA expression data retrieved from the National Center for Biotechnology Information's Gene Expression Omnibus (GEO) database, which was normalized against 60 abundantly and commonly found proteins, indicated altered expression for this protein kinase as shown here as the percent change from normal tissue controls (%CFC) as supported with the Student T-test in the following types of human cancers: Bladder carcinomas (%CFC= +65, p<0.001); Brain glioblastomas (%CFC= -65, p<0.011); Cervical cancer (%CFC= +46, p<0.004); Clear cell renal cell carcinomas (cRCC) stage I (%CFC= +258, p<(0.0003); Ovary adenocarcinomas (%CFC= +45, p<0.025); Prostate cancer - metastatic (%CFC= -57, p<0.0001); Prostate cancer - primary (%CFC= +136, p<0.0001); Skin melanomas - malignant (%CFC= +95, p<0.0004). The COSMIC website notes an up-regulated expression score for RIPK1 in diverse human cancers of 472, which is close to the average score of 462 for the human protein kinases. The down-regulated expression score of 450 for this protein kinase in human cancers was 7.5-fold of the average score of 60 for the human protein kinases.
Mutagenesis Experiments:
Insertional mutagenesis studies in mice have not yet revealed a role for this protein kinase in mouse cancer oncogenesis. RIPK1 phosphotransferase activity can be impaired with a K45A mutation. A S161A mutation can decrease the phosphotransferase activity of RIPK1. A S161E mutation has no effect on autophosphorylation of RIPK1. Caspase-8-mediated RIPK1 cleavage is impaired through a D324K mutation. NF-kB induction through RIPK1 can be inhibited via a K377R mutation.
Mutation Rate in All Cancers:
Percent mutation rates per 100 amino acids length in human cancers: 0.06 % in 25588 diverse cancer specimens. This rate is only -19 % lower than the average rate of 0.075 % calculated for human protein kinases in general.
Mutation Rate in Specific Cancers:
Highest percent mutation rates per 100 amino acids length in human cancers: 0.26 % in 1270 large intestine cancers tested; 0.25 % in 603 endometrium cancers tested; 0.16 % in 273 cervix cancers tested; 0.15 % in 589 stomach cancers tested; 0.14 % in 864 skin cancers tested; 0.14 % in 1512 liver cancers tested; 0.13 % in 238 bone cancers tested; 0.08 % in 548 urinary tract cancers tested; 0.08 % in 1634 lung cancers tested; 0.07 % in 1316 breast cancers tested; 0.04 % in 710 oesophagus cancers tested; 0.04 % in 2009 haematopoietic and lymphoid cancers tested; 0.04 % in 1459 pancreas cancers tested; 0.04 % in 1276 kidney cancers tested; 0.03 % in 942 upper aerodigestive tract cancers tested; 0.03 % in 881 prostate cancers tested; 0.02 % in 2103 central nervous system cancers tested.
Frequency of Mutated Sites:
None > 3 in 20,721 cancer specimens
Comments:
Only 1 deletion, and no insertions or complex mutations are noted on the COSMIC website.