KinaseNET

Nomenclature

Short Name:

IRAK4

Full Name:

Interleukin-1 receptor-associated kinase-4

Alias:

EC 2.7.11.1
NY-REN-64
Interleukin-1 receptor associated kinase 4
IRAK-4
IPD1
REN64

Classification

Type:

Protein-serine/threonine kinase

Group:

TKL

Family:

IRAK

SubFamily:

Specific Links

Entrez-Gene Entry:	51135
Entrez-Protein Entry:	NP_057207
GeneCards Entry:	NYREN64
KinBASE Entry:	IRAK4
OMIM Entry:	606883
PhosphoNET Entry:	Q9NWZ3
Phosphosite Plus Entry:	1998
Protein Data Bank Entry:	2NRU
Source Entry:	IRAK4
UCSD-Nature Entry:	A003450
UniProt Entry:	Q9NWZ3
Kinexus Products:	IRAK4 Interleukin 1 receptor-associated kinase 4 T345+S346 phosphosite-specific antibody AB-PK665 Interleukin 1 receptor-associated kinase 4 (T342-V349, human) pT345+pS346 phosphopeptide - Powder PE-04ANA99 Interleukin 1 receptor-associated kinase 4 (F439-M455, human) pT342+pT345+pS346+pT351+pT352+pY354 phosphopeptide - Powder PE-04AVI85

General Links

Structure

Mol. Mass (Da):

51,530

# Amino Acids:

460

# mRNA Isoforms:

mRNA Isoforms:

51,530 Da (460 AA; Q9NWZ3); 37,674 Da (336 AA; Q9NWZ3-2)

4D Structure:

IL-1 stimulation leads to the formation of a signaling complex which dissociates from the IL-1 receptor following the binding of PELI1. Interacts with IL1RL1.

1D Structure:

Retrieve Gene Sequence
Retrieve Full Protein Sequence
Retrieve Catalytic Domain Sequence

3D Image (rendered using PV Viewer):

PDB ID

2NRU

Subfamily Alignment

Domain Distribution:

Start	End	Domain
20	104	Death
186	454	Pkinase

Kinexus Products

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

hiddentext

○	Interleukin 1 receptor-associated kinase 4 T345+S346 phosphosite-specific antibody AB-PK665
○	Interleukin 1 receptor-associated kinase 4 (T342-V349, human) pT345+pS346 phosphopeptide - Powder PE-04ANA99
○	Interleukin 1 receptor-associated kinase 4 (F439-M455, human) pT342+pT345+pS346+pT351+pT352+pY354 phosphopeptide - Powder PE-04AVI85

Post-translation Modifications

For detailed information on phosphorylation of this kinase go to PhosphoNET

Acetylated:

K3 (N6), K34 (N6).

Serine phosphorylated:

S8, S114, S150, S151, S152, S157, S336, S346+.

Threonine phosphorylated:

T6, T208, T209, T342+, T345+, T352.

Tyrosine phosphorylated:

Y354, Y430.

Distribution

Based on gene microarray analysis from the NCBI

Human Tissue Distribution

% Max Expression:

Mean Expression:

Number of Samples:

Standard Deviation:

23

875

16

1092
0.5

18

8

15
1

37

1

0
6

236

40

403
18

681

14

681
1

40

37

11
1

40

15

17
11

444

15

528
12

454

10

452
0.9

33

33

13
1.2

48

12

37
18

696

74

560
2

81

12

15
0.7

28

6

17
2

61

9

46
0.9

36

7

10
1.3

52

15

33
1

37

6

29
1.2

47

37

26
15

576

56

624
0.8

30

8

28
2

62

10

37
2

72

2

34
0.7

29

6

25
2

83

8

83
16

608

22

623
2

66

15

30
0.7

26

6

24
0.6

25

6

22
4

149

14

70
26

1000

18

662
100

3876

19

7176
3

100

51

288
23

903

26

740
3

104

22

76

Evolution

Species Conservation

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

100

100

100
99.1

99.6

99
98.7

99.1

99
-

-

90
-

-

95
92.8

96.3

93
-

-

-
83.9

90.9

84
84.4

92

84.5
-

-

-
45.2

52

-
47.4

58.3

67
-

-

63
39.1

54.8

48
-

-

-
-

-

-
-

-

-
-

-

-
33.9

51.1

-
28.1

47.5

-
-

-

-
-

-

39
21.6

34.4

45
-

-

-
-

-

-

For a wider analysis go to PhosphoNET Evolution in PhosphoNET

Binding Proteins

Examples of known interacting proteins

hiddentext

No.	Name – UniProt ID
1	PELI2 - Q9HAT8
2	IL1RL1 - Q01638

Regulation

Activation:

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

IRAK4	Q9NWZ3	T6	__MNKPITPSTYVRC
IRAK4	Q9NWZ3	S8	MNKPITPSTYVRCLN
IRAK4	Q9NWZ3	S114	KTANTLPSKEAITVQ
IRAK4	Q9NWZ3	S150	QSYMPPDSSSPENKS
IRAK4	Q9NWZ3	S151	SYMPPDSSSPENKSL
IRAK4	Q9NWZ3	S152	YMPPDSSSPENKSLE
IRAK4	Q9NWZ3	T208	YKGYVNNTTVAVKKL
IRAK4	Q9NWZ3	T209	KGYVNNTTVAVKKLA
IRAK4	Q9NWZ3	T342	ASEKFAQTVMTSRIV	+
IRAK4	Q9NWZ3	T345	KFAQTVMTSRIVGTT	+
IRAK4	Q9NWZ3	S346	FAQTVMTSRIVGTTA	+

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

IRAK1	P51617	S376	GSSPSQSSMVARTQT	+
IRAK1	P51617	T209	LCEISRGTHNFSEEL	+
IRAK1	P51617	T387	RTQTVRGTLAYLPEE	+
IRAK4	Q9NWZ3	S114	KTANTLPSKEAITVQ
IRAK4	Q9NWZ3	S150	QSYMPPDSSSPENKS
IRAK4	Q9NWZ3	S151	SYMPPDSSSPENKSL
IRAK4	Q9NWZ3	S152	YMPPDSSSPENKSLE
IRAK4	Q9NWZ3	S346	FAQTVMTSRIVGTTA	+
IRAK4	Q9NWZ3	S8	MNKPITPSTYVRCLN
IRAK4	Q9NWZ3	T208	YKGYVNNTTVAVKKL
IRAK4	Q9NWZ3	T209	KGYVNNTTVAVKKLA
IRAK4	Q9NWZ3	T342	ASEKFAQTVMTSRIV	+
IRAK4	Q9NWZ3	T345	KFAQTVMTSRIVGTT	+
IRAK4	Q9NWZ3	T6	__MNKPITPSTYVRC
p47phox	P14598	S320	QRSRKRLSQDAYRRN	?
p47phox	P14598	S345	QARPGPQSPGSPLEE	+
p47phox	P14598	S348	PGPQSPGSPLEEERQ
p47phox	P14598	S359	EERQTQRSKPQPAVP	+
p47phox	P14598	S370	PAVPPRPSADLILNR	+
PELI1	Q96FA3	S293	FNTLAFPSMKRKDVV	+
PELI1	Q96FA3	S70	PQAAKAISNKDQHSI
PELI1	Q96FA3	S76	ISNKDQHSISYTLSR	+
PELI1	Q96FA3	S78	NKDQHSISYTLSRAQ	+
PELI1	Q96FA3	S82	HSISYTLSRAQTVVV	+
PELI1	Q96FA3	T127	GSQSNSDTQSVQSTI
PELI1	Q96FA3	T288	QCPVGFNTLAFPSMK	+
PELI1	Q96FA3	T80	DQHSISYTLSRAQTV	+
PELI1	Q96FA3	T86	YTLSRAQTVVVEYTH	+

Protein Kinase Specificity

Matrix of observed frequency (%) of amino acids in aligned protein substrate phosphosites

Matrix Type:

Experimentally derived from alignment of 32 known protein substrate phosphosites.

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

Lestaurtinib	Kd = 1.7 nM	126565		22037378
Staurosporine	Kd = 1.7 nM	5279		22037378
TTT-3002	IC50 < 2 nM
K-252a; Nocardiopsis sp.	IC50 < 25 nM	3813	281948	22037377
Syk Inhibitor	IC50 < 25 nM	6419747	104279	22037377
GSK650394A	IC50 < 40 nM	25022668	558642
IRAK-4 kinase inhibitor a	IC50 < 40 nM
Princeton's TrkA inhibitor compound 20h	IC50 < 40 nM
JAK3 Inhibitor VI	IC50 > 50 nM	16760524		22037377
SB218078	IC50 > 50 nM	447446	289422	22037377
Sunitinib	Kd = 66 nM	5329102	535	22037378
Vandetanib	Kd = 75 nM	3081361	24828	22037378
NVP-TAE684	Kd = 77 nM	16038120	509032	22037378
IRAK-4 kinase inhibitor b	IC50 < 80 nM
SU14813	Kd = 82 nM	10138259	1721885	22037378
AT9283	IC50 > 100 nM	24905142		19143567
BCP9000822	IC50 = 100 nM	5278396	222102
IRAK-1-4 Inhibitor I	IC50 < 100 nM	11983295	379787
Purvalanol A	IC50 = 100 nM	456214	23327
Staurosporine aglycone	IC50 < 100 nM	3035817	281948
SU6656	IC50 < 100 nM	5353978	605003
Dovitinib	Kd = 130 nM	57336746		22037378
Cdk1/2 Inhibitor III	IC50 > 150 nM	5330812	261720	22037377
SU11652	IC50 > 150 nM	24906267	13485	22037377
Bosutinib	Kd = 360 nM	5328940	288441	22037378
Amgen TBK 1 inhibitor (Compound II)	IC50 < 400 nM
GW441756 hydrochloride	IC50 < 400 nM	16219400
IKK-3 inhibitor IX	IC50 < 400 nM	11626927	373751
Purvalanol B	IC50 < 400 nM	448991	23254
Semaxinib	IC50 = 500 nM	5329098	276711	22037377
Gefitinib	Kd = 540 nM	123631	939	22037378
BX795	IC50 < 600 nM	10077147	577784
GSK-3 Inhibitor IX	IC50 > 600 nM	5287844	409450
PP242	IC50 < 600 nM	25243800
R406	IC50 < 600 nM	11984591
KW2449	Kd = 680 nM	11427553	1908397	22037378
AG1478	IC50 < 800 nM	2051	7917
BI-D1870	IC50 < 800 nM	25023738	573107
Ro-31-8220	IC50 < 800 nM	5083	6291
Nintedanib	Kd = 810 nM	9809715	502835	22037378
A 443654	IC50 = 1 µM	10172943	379300	19465931
BML-275	IC50 = 1 µM	11524144	478629
CHEMBL1650545	IC50 = 1 µM	53316611	1650545	21128646
Gö6976	IC50 > 1 µM	3501	302449	22037377
Hypothemycin	IC50 = 1 µM	5477775	471474
IDR E804	IC50 > 1 µM	6419764	1802727	22037377
IPA-3	IC50 = 1 µM	521106	472940
MK5108	IC50 > 1 µM	24748204		20053775
PKR Inhibitor	IC50 > 1 µM	6490494	235641	22037377
Silmitasertib	IC50 > 1 µM	24748573		21174434
SNS314	IC50 > 1 µM	16047143	514582	18678489
SU11274	IC50 > 1 µM	9549297	261641	22037377
SureCN10063060	Ki > 1 µM	52936621		21391610
VEGFR2 Kinase Inhibitor II	IC50 > 1 µM	5329155	88606	22037377
Wyeth PDK1 Inhibitor Compound 1	IC50 = 1 µM
WZ3146	Kd > 1 µM	44607360		20033049
WZ4002	Kd > 1 µM	44607530		20033049
Canertinib	Kd = 1.2 µM	156414	31965	22037378
TG101348	Kd = 1.2 µM	16722836	1287853	22037378
Alvocidib	Kd = 1.5 µM	9910986	428690	22037378
Momelotinib	IC50 > 2 µM	25062766		19295546
BI2536	Kd = 2.1 µM	11364421	513909	22037378
CHEMBL494221	Ki > 2.3 µM	5328125	494221	19414255
A674563	Kd = 2.5 µM	11314340	379218	22037378
PHA-665752	Kd = 2.5 µM	10461815	450786	22037378
Syk Inhibitor II	IC50 > 3 µM	16760670
TG101209	IC50 > 3 µM	16722832		17541402
SureCN4875304	IC50 > 3.5 µM	46871765		20472445
Crizotinib	Kd = 3.6 µM	11626560	601719	22037378
Tozasertib	Kd = 3.7 µM	5494449	572878	22037378
CHEMBL493169	Ki > 4 µM	44219632	493169	19414255
CZC-25146	IC50 < 4 µM
IKK-2 Inhibitor IV	IC50 < 4 µM	9903786	257167
JNJ-28871063	IC50 > 4 µM	17747413		17975007
Pyrimidylpyrrole, 11e	Ki > 4 µM	11634725	583042	19827834
GDC-0941	IC50 > 4.5 µM	17755052	521851
Syk Inhibitor IV	IC50 > 4.5 µM	10200390
Tofacitinib	IC50 > 4.5 µM	9926791	221959

Disease Linkage

General Disease Association:

Immune disorders

Specific Diseases (Non-cancerous):

Irak-4 deficiency; Pneumococcal meningitis; Invasive pneumococcal disease, Recurrent isolated, 1

Comments:

IRAK4 deficiency is a rare immunodeficiency condition resulting in severe recurring infections with pyogenic bacteria (inducing pus production), especially Streptococcus pneumoniae. IRAK4 deficiency is linked to TLR signalling and NF-kappaB pathways.

Gene Expression in Cancers:

The COSMIC website notes an up-regulated expression score for IRAK4 in diverse human cancers of 397, which is 0.9-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 125 for this protein kinase in human cancers was 2.1-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: 0.05 % in 25335 diverse cancer specimens. This rate is only -30 % 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: 0.29 % in 603 endometrium cancers tested; 0.21 % in 1270 large intestine cancers tested; 0.2 % in 864 skin cancers tested; 0.18 % in 238 bone cancers tested; 0.11 % in 575 stomach cancers tested; 0.08 % in 558 thyroid cancers tested; 0.08 % in 548 urinary tract cancers tested; 0.07 % in 1512 liver cancers tested; 0.06 % in 710 oesophagus cancers tested; 0.06 % in 1956 lung cancers tested; 0.04 % in 1490 breast cancers tested; 0.03 % in 2060 central nervous system cancers tested; 0.03 % in 2009 haematopoietic and lymphoid cancers tested; 0.02 % in 939 prostate cancers tested; 0.02 % in 891 ovary cancers tested; 0.02 % in 1276 kidney cancers tested; 0 % in 958 upper aerodigestive tract cancers tested.

Frequency of Mutated Sites:

Most frequent mutations with the number of reports indicated in brackets: R12C (3).

Comments:

Only 5 deletions, and no insertions or complex mutations are noted on the COSMIC website.

COSMIC Entry:

IRAK4

OMIM Entry:

606883

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

Acetylated:

Serine phosphorylated:

Threonine phosphorylated:

Tyrosine phosphorylated:

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

General Disease Association:

Specific Diseases (Non-cancerous):

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: