KinaseNET

Nomenclature

Short Name:

RIPK2

Full Name:

Receptor-interacting serine-threonine-protein kinase 2

Alias:

CARD3
EC 2.7.11.1
GIG30
RICK
RIP2
Kinase RIPK2; Receptor-interacting protein 2; Receptor-interacting serine/threonine protein kinase 2; RIP-like-interacting CLARP kinase
CARD-containing IL-1 beta ICE-kinase
CARD-containing interleukin-1 beta converting enzyme associated kinase
CARD-containing interleukin-1 beta-converting enzyme-associated kinase
CARDIAK

Classification

Type:

Protein-serine/threonine kinase

Group:

TKL

Family:

RIPK

SubFamily:

Specific Links

BioCarta Entry:	fas pathway
Entrez-Gene Entry:	8767
Entrez-Protein Entry:	NP_003812
GeneCards Entry:	RIP2
KinBASE Entry:	RIPK2
OMIM Entry:	603455
Pfam Entry:	O43353
PhosphoNET Entry:	O43353
Phosphosite Plus Entry:	751
ScanSite Entry:	O43353
Source Entry:	RIPK2
UCSD-Nature Entry:	A002083
UniProt Entry:	O43353
Kinexus Products:	RIPK2 Receptor-interacting serine/threonine-protein kinase 2 (RIPK2) S176 phosphosite-specific antibody AB-PK796 Receptor-interacting serine/threonine-protein kinase 2 (RIPK2) Y381 phosphosite-specific antibody AB-PK797 Receptor-interacting serine/threonine-protein kinase 2 (RIPK2) (M173-R179, human) pS176 phosphopeptide - Powder PE-04API75 Receptor-interacting serine/threonine-protein kinase 2 (RIPK2) (Q378-K384, human) pY381 phosphopeptide - Powder PE-04APJ90

General Links

Structure

Mol. Mass (Da):

61,195

# Amino Acids:

540

# mRNA Isoforms:

mRNA Isoforms:

61,195 Da (540 AA; O43353); 45,582 Da (403 AA; O43353-2)

4D Structure:

Binds to CFLAR/CLARP and CASP1 via their CARD domains. Binds to BIRC3/c-IAP1 and BIRC2/c-IAP2, TRAF1, TRAF2, TRAF5 and TRAF6. May be a component of both the TNFRSF1A and TNRFSF5/CD40 receptor complex. Interacts with NOD2.

1D Structure:

Retrieve Gene Sequence
Retrieve Full Protein Sequence
Retrieve Catalytic Domain Sequence

3D Image (rendered using PV Viewer):

PDB ID

5AR2

Subfamily Alignment

Domain Distribution:

Start	End	Domain
18	294	Pkinase
432	524	CARD

Kinexus Products

Click on entries below for direct links to relevant products from Kinexus for this protein kinase.

hiddentext

○	Receptor-interacting serine/threonine-protein kinase 2 (RIPK2) S176 phosphosite-specific antibody AB-PK796
○	Receptor-interacting serine/threonine-protein kinase 2 (RIPK2) Y381 phosphosite-specific antibody AB-PK797
○	Receptor-interacting serine/threonine-protein kinase 2 (RIPK2) (M173-R179, human) pS176 phosphopeptide - Powder PE-04API75
○	Receptor-interacting serine/threonine-protein kinase 2 (RIPK2) (Q378-K384, human) pY381 phosphopeptide - Powder PE-04APJ90

Post-translation Modifications

For detailed information on phosphorylation of this kinase go to PhosphoNET

Serine phosphorylated:

S168, S174, S176+, S178+, S181+, S345, S357, S363, S393, S527, S529, S531, S539.

Threonine phosphorylated:

T411.

Tyrosine phosphorylated:

Y23, Y381, Y474+.

Ubiquitinated:

K17, K182, K203, K209.

Distribution

Based on gene microarray analysis from the NCBI

Human Tissue Distribution

% Max Expression:

Mean Expression:

Number of Samples:

Standard Deviation:

50

925

29

1064
3

50

15

81
3

52

12

32
21

395

89

793
38

708

24

563
4

65

74

61
8

145

31

285
71

1312

39

3064
18

328

17

264
3

58

83

60
3

55

31

84
36

658

163

620
4

67

34

50
2

43

10

60
3

60

14

94
2

42

15

37
1.4

26

119

42
4

76

21

72
2

34

87

39
31

564

109

575
6

111

23

87
3

64

26

61
3

54

14

47
2

44

20

60
2

35

23

47
46

842

57

1580
3

59

37

64
4

68

20

65
4

71

20

65
6

103

28

84
43

798

24

762
100

1849

36

3323
8

142

71

258
59

1082

52

741
3

54

35

62

Evolution

Species Conservation

PhosphoNET % Identity:
PhosphoNET % Similarity:
Homologene %
Identity:

100

100

100
99.3

99.4

99
97.4

97.8

97
-

-

87.5
-

-

-
86.7

90.7

87
-

-

-
84.3

89.8

84
24.8

40.9

85
-

-

-
25.7

39.7

-
63.4

74.2

69
26

44.3

59
49.3

64.7

54
-

-

-
-

-

-
-

-

-
-

-

-
-

-

-
-

-

-
-

-

-
-

-

-
-

-

-
-

-

-
-

-

-

For a wider analysis go to PhosphoNET Evolution in PhosphoNET

Binding Proteins

Examples of known interacting proteins

hiddentext

No.	Name – UniProt ID
1	NOD1 - Q9Y239
2	CARD16 - Q5EG05
3	BIRC2 - Q13490
4	NOD2 - Q9HC29
5	TLR4 - O00206
6	TLR2 - O60603
7	NGFR - P08138
8	CFLAR - O15519
9	BCL10 - O95999
10	IKBKG - Q9Y6K9
11	CASP8 - Q14790
12	IRAK1 - P51617
13	TNFRSF1A - P19438
14	TRAF1 - Q13077
15	TRAF6 - Q9Y4K3

Regulation

Activation:

Activated by phosphorylation at Ser-176.

Inhibition:

Synthesis:

Degradation:

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

RIPK2	O43353	S176	KWRMMSLSQSRSSKS	+
RIPK2	O43353	Y474	DLIMKEDYELVSTKP	+

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

RIPK2	O43353	S176	KWRMMSLSQSRSSKS	+
RIPK2	O43353	Y474	DLIMKEDYELVSTKP	+

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 #:

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

Vandetanib	Kd = 4.6 nM	3081361	24828	18183025
CHEMBL249097	Kd < 10 nM	25138012	249097	19035792
SureCN7018367	Kd < 10 nM	18792927	450519	19035792
PD173955	Kd = 16 nM	447077	386051	22037378
SB203580	IC50 = 16 nM	176155	10	15943486
PP2	IC50 = 19 nM	4878	406845	17850214
Foretinib	Kd = 21 nM	42642645	1230609	22037378
Src Kinase Inhibitor I	IC50 = 26 nM	1474853	97771	17850214
Dasatinib	Kd = 31 nM	11153014	1421	18183025
Princeton's TrkA inhibitor compound 20h	IC50 < 40 nM
K-252a; Nocardiopsis sp.	IC50 > 50 nM	3813	281948	22037377
A-83-01	IC50 < 60 nM	16218924	1170377
Amgen TBK 1 inhibitor (Compound II)	IC50 < 60 nM
BML-275	IC50 < 60 nM	11524144	478629
Ibrutinib	IC50 < 60 nM	24821094	1873475
KIN 112	IC50 < 60 nM
SB590885	IC50 < 60 nM	11465183	477989
STO609	IC50 < 60 nM	51371511
TTT-3002	IC50 < 60 nM
HG-9-91-01	IC50 < 80 nM
Cediranib	Kd = 98 nM	9933475	491473	22037378
AG1478	IC50 < 100 nM	2051	7917
AT9283	IC50 > 100 nM	24905142		19143567
GSK650394A	IC50 = 100 nM	25022668	558642
LDN193189	IC50 = 100 nM	25195294	513147
PP242	IC50 = 100 nM	25243800
Staurosporine aglycone	IC50 < 100 nM	3035817	281948
PP1 Analog II; 1NM-PP1	IC50 = 130 nM	5154691	573578	17850214
Alsterpaullone; 2-Cyanoethyl	IC50 > 150 nM	16760286	260138	22037377
Cdk1/2 Inhibitor III	IC50 > 150 nM	5330812	261720	22037377
Lck Inhibitor	IC50 > 150 nM	6603792		22037377
SB202190	Kd = 150 nM	5353940	278041	18183025
Syk Inhibitor IV	IC50 = 200 nM	10200390
AG1024	IC50 > 250 nM	2044		22037377
Alsterpaullone	IC50 > 250 nM	5005498	50894	22037377
BCP9000906	IC50 > 250 nM	5494425	21156	22037377
BPIQ-I	IC50 > 250 nM	2427		22037377
Compound 56	IC50 > 250 nM	2857	29197	22037377
Flt-3 Inhibitor II	IC50 > 250 nM	11601743	377193	22037377
HDS029	IC50 > 250 nM	11566580	203644	22037377
PD169316	IC50 > 250 nM	4712	17331	22037377
TWS119	IC50 > 250 nM	9549289	405759	22037377
WHI-P154	IC50 > 250 nM	3795	473773	22037377
Canertinib	Kd = 300 nM	156414	31965	18183025
Aurora A Inhibitor 23 (DF)	Kd < 400 nM			21992004
Curcumin	IC50 < 400 nM	5281767	116438
IKK-3 inhibitor IX	IC50 < 400 nM	11626927	373751
LY364947	IC50 < 400 nM	447966	261454
Erlotinib	Kd = 410 nM	176870	553	15711537
PLX4720	Kd = 430 nM	24180719	1230020	22037378
D4476	IC50 = 500 nM	6419753	410456	22037377
Flt-3 Inhibitor III	IC50 = 500 nM	11772958		22037377
Gö6976	IC50 = 500 nM	3501	302449	22037377
JAK3 Inhibitor VI	IC50 = 500 nM	16760524		22037377
p38 MAP Kinase Inhibitor	IC50 = 500 nM	4665	91730	22037377
PKR Inhibitor; Negative Control	IC50 = 500 nM	16760619		22037377
Staurosporine	IC50 = 500 nM	5279		22037377
Gefitinib	Kd = 530 nM	123631	939	18183025
Pazopanib	Kd = 580 nM	10113978	477772	18183025
GW 843682X	IC50 < 600 nM	9826308	514499
R406	IC50 < 600 nM	11984591
SB505124	IC50 < 600 nM	16079009	1835714
Syk Inhibitor	IC50 < 600 nM	6419747	104279
Lestaurtinib	Kd = 640 nM	126565		22037378
K00596a	IC50 < 800 nM	9549298	200027
SB431542	IC50 < 800 nM	4521392
Crizotinib	Kd = 900 nM	11626560	601719	22037378
GSK-3 Inhibitor IX	IC50 > 900 nM	5287844	409450
RAF265	Kd = 950 nM	11656518	558752	18183025
4557W	IC50 > 1 µM	9843206	563845	22037377
AG-E-60384	IC50 > 1 µM	6419741	413188	22037377
Akt Inhibitor VIII	IC50 = 1 µM	10196499	258844
Aloisine A	IC50 > 1 µM	5326843	75680	22037377
AS601245	IC50 > 1 µM	11422035	191384	22037377
CHEMBL566515	Kd < 1 µM	44478401	566515	19788238
ETP 46464	IC50 = 1 µM
GSK2578215A	IC50 = 1 µM
IDR E804	IC50 > 1 µM	6419764	1802727	22037377
JNKIN7	IC50 = 1 µM	57340685
JNKIN8	IC50 = 1 µM	57340686
MK5108	IC50 > 1 µM	24748204		20053775
MNK1 Inhibitor	IC50 > 1 µM	11644425	1240885	22037377
PD158780	IC50 > 1 µM	4707	53753	22037377
Silmitasertib	IC50 > 1 µM	24748573		21174434
SNS314	IC50 > 1 µM	16047143	514582	18678489
SU6656	IC50 = 1 µM	5353978	605003
VEGFR2 Kinase Inhibitor IV	IC50 > 1 µM	5329468	92461	22037377
WZ3146	Kd > 1 µM	44607360		20033049
WZ4002	Kd > 1 µM	44607530		20033049
AST-487	Kd = 1.1 µM	11409972	574738	18183025
Sorafenib	Kd = 1.3 µM	216239	1336	18183025
Barasertib	Kd = 1.8 µM	16007391	215152	18183025
Quercetagetin	IC50 < 2 µM	5281680	413552
GDC0879	Kd = 2.5 µM	11717001	525191	22037378
Hesperadin	Kd < 2.5 µM	10142586	514409	19035792
Afatinib	Kd = 2.7 µM	10184653	1173655	22037378
Quizartinib	Kd = 2.7 µM	24889392	576982	22037378
Brivanib	Kd = 2.9 µM	11234052	377300	22037378
GSK461364A	IC50 > 3 µM	15983966	1908394
GW441756 hydrochloride	IC50 > 3 µM	16219400
Syk Inhibitor II	IC50 > 3 µM	16760670
Wyeth PDK1 Inhibitor Compound 1	IC50 > 3 µM
SB431542	Kd = 3.4 µM	4521392	440084	18183025
Lapatinib	Kd = 3.6 µM	208908	554	18183025
Bosutinib	Kd = 3.7 µM	5328940	288441	22037378
KW2449	Kd = 3.7 µM	11427553	1908397	22037378
BMS-690514	Kd < 4 µM	11349170		21531814
JNJ-28871063	IC50 > 4 µM	17747413		17975007
BX795	IC50 > 4.5 µM	10077147	577784

Disease Linkage

Comments:

RIPK2 variants were shown to associate with susceptibility to Mycobacterium leprae in Indian populations.

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: Classical Hodgkin lymphomas (%CFC= +56, p<0.086); Colon mucosal cell adenomas (%CFC= +102, p<0.0001); Large B-cell lymphomas (%CFC= +78, p<0.052); Malignant pleural mesotheliomas (MPM) tumours (%CFC= +107, p<0.009). The COSMIC website notes an up-regulated expression score for RIPK2 in diverse human cancers of 830, which is 1.8-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 8 for this protein kinase in human cancers was 0.1-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.

Mutation Rate in All Cancers:

Percent mutation rates per 100 amino acids length in human cancers: 0.06 % in 24945 diverse cancer specimens. This rate is only -16 % 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: 0.28 % in 1270 large intestine cancers tested; 0.26 % in 864 skin cancers tested; 0.21 % in 603 endometrium cancers tested; 0.19 % in 589 stomach cancers tested; 0.1 % in 710 oesophagus cancers tested; 0.1 % in 548 urinary tract cancers tested; 0.07 % in 833 ovary cancers tested; 0.07 % in 273 cervix cancers tested; 0.07 % in 1512 liver cancers tested; 0.07 % in 1276 kidney cancers tested; 0.06 % in 881 prostate cancers tested; 0.06 % in 1316 breast cancers tested; 0.05 % in 1634 lung cancers tested; 0.05 % in 1459 pancreas cancers tested; 0.04 % in 942 upper aerodigestive tract cancers tested; 0.01 % in 2103 central nervous system cancers tested.

Frequency of Mutated Sites:

None > 1 in 20,197 cancer specimens

Comments:

Only 1 insertion, and no deletions or complex mutations are noted in COSMIC website.

COSMIC Entry:

RIPK2

OMIM Entry:

603455

Nomenclature

Short Name:

Full Name:

Alias:

Classification

Type:

Group:

Family:

SubFamily:

Specific Links

General Links

Structure

Mol. Mass (Da):

# Amino Acids:

# mRNA Isoforms:

mRNA Isoforms:

4D Structure:

1D Structure:

3D Image (rendered using PV Viewer):

PDB ID

Subfamily Alignment

Domain Distribution:

Kinexus Products

hiddentext

Post-translation Modifications

Serine phosphorylated:

Threonine phosphorylated:

Tyrosine phosphorylated:

Ubiquitinated:

Distribution

Human Tissue Distribution

% Max Expression: Mean Expression: Number of Samples: Standard Deviation:

% Max Expression: Mean Expression: Number of Samples: Standard Deviation:

Evolution

Species Conservation

PhosphoNET % Identity: PhosphoNET % Similarity: Homologene %Identity:

PhosphoNET % Identity: PhosphoNET % Similarity: Homologene %Identity:

Binding Proteins

hiddentext

Regulation

Activation:

Inhibition:

Synthesis:

Degradation:

Known Upstream Kinases

Based on in vitro and/or in vivo phosphorylation data

Known Downstream Substrates

Based on in vitro and/or in vivo phosphorylation data

Protein Kinase Specificity

Matrix Type:

Domain #:

Inhibitors

Based on in vitro and/or in vivo phosphorylation data

Disease Linkage

Comments:

Gene Expression in Cancers:

Mutagenesis Experiments:

Mutation Rate in All Cancers:

Mutation Rate in Specific Cancers:

Frequency of Mutated Sites:

Comments:

COSMIC Entry:

OMIM Entry:

% Max Expression:

Mean Expression:

Number of Samples:

Standard Deviation:

% Max Expression:

Mean Expression:

Number of Samples:

Standard Deviation:

PhosphoNET % Identity:
PhosphoNET % Similarity:
Homologene %
Identity:

PhosphoNET % Identity:
PhosphoNET % Similarity:
Homologene %
Identity: