KinaseNET

Nomenclature

Short Name:

TRKB

Full Name:

BDNF-NT-3 growth factors receptor

Alias:

EC 2.7.10.1
GP145-TrkB
GP145-TrkB,GP95-TrkB
NTRK2

Classification

Type:

Protein-tyrosine kinase

Group:

Family:

Trk

SubFamily:

Specific Links

Entrez-Gene Entry:	4915
Entrez-Protein Entry:	NP_001018074
GeneCards Entry:	TRKB
KinBASE Entry:	TRKB
OMIM Entry:	600456
Pfam Entry:	Q16620
PhosphoNET Entry:	Q16620
Phosphosite Plus Entry:	1975
Protein Data Bank Entry:	1HCF
ScanSite Entry:	Q16620
Source Entry:	NTRK2
UCSD-Nature Entry:	A002320
UniProt Entry:	Q16620
Kinexus Products:	TRKB BNDF/NT3/4/5 receptor- tyrosine kinase Y516 phosphosite-specific antibody AB-PK838 BNDF/NT3/4/5 receptor- tyrosine kinase Y702 phosphosite-specific antibody AB-PK839 BNDF/NT3/4/5 receptor- tyrosine kinase (N513-I519, human) pY516 phosphopeptide - Powder PE-04AQD80 BNDF/NT3/4/5 receptor- tyrosine kinase (R699-D705, human) pY702 phosphopeptide - Powder PE-04AQE95

General Links

Structure

Mol. Mass (Da):

91,999

# Amino Acids:

822

# mRNA Isoforms:

mRNA Isoforms:

93,826 Da (838 AA; Q16620-4); 91,999 Da (822 AA; Q16620); 81,569 Da (735 AA; Q16620-6); 60,994 Da (553 AA; Q16620-5); 59,167 Da (537 AA; Q16620-3); 53,051 Da (477 AA; Q16620-2); 35,332 Da (321 AA; Q16620-7)

4D Structure:

Exists in a dynamic equilibrium between monomeric (low affinity) and dimeric (high affinity) structures. Binds SH2B2. Interacts with SQSTM1 and KIDINS220

1D Structure:

Retrieve Gene Sequence
Retrieve Full Protein Sequence
Retrieve Catalytic Domain Sequence

3D Image (rendered using PV Viewer):

PDB ID

4ASZ

Subfamily Alignment

Domain Distribution:

Start	End	Domain
1	32	signal_peptide
31	65	LRRNT
92	115	LRR
116	139	LRR
148	195	LRRCT
197	282	IGc2
432	454	TMD
538	807	TyrKc
538	809	Pkinase

Kinexus Products

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

hiddentext

○	BNDF/NT3/4/5 receptor- tyrosine kinase Y516 phosphosite-specific antibody AB-PK838
○	BNDF/NT3/4/5 receptor- tyrosine kinase Y702 phosphosite-specific antibody AB-PK839
○	BNDF/NT3/4/5 receptor- tyrosine kinase (N513-I519, human) pY516 phosphopeptide - Powder PE-04AQD80
○	BNDF/NT3/4/5 receptor- tyrosine kinase (R699-D705, human) pY702 phosphopeptide - Powder PE-04AQE95

Post-translation Modifications

For detailed information on phosphorylation of this kinase go to PhosphoNET

Acetylated:

K461.

N-GlcNAcylated:

N67,N95, N121, N178, N205, N241, N254, N280, N325, N338, N412.

Serine phosphorylated:

S141, S153, S256, S257, S260, S479, S698+, S703+.

Threonine phosphorylated:

T151, T161, T253, T506, T573.

Tyrosine phosphorylated:

Y516+, Y558, Y702+, Y706+, Y707+, Y817.

Distribution

Based on gene microarray analysis from the NCBI

Human Tissue Distribution

% Max Expression:

Mean Expression:

Number of Samples:

Standard Deviation:

85

962

67

1149
3

39

33

61
9

100

20

118
79

898

269

993
81

926

62

790
11

125

181

281
22

245

91

437
34

384

100

661
26

291

31

201
8

92

257

108
3

33

75

39
44

503

419

597
7

82

64

76
4

50

29

39
6

72

50

83
3

36

43

49
2

26

860

113
9

98

39

142
5

54

221

59
48

549

271

573
46

529

63

992
5

57

68

79
3

36

48

47
4

49

40

57
3

36

61

47
68

774

162

938
6

66

63

88
10

119

40

149
7

77

39

102
13

153

84

213
25

282

48

280
100

1138

76

2580
12

140

141

468
57

650

171

627
4

46

87

44

Evolution

Species Conservation

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

100

100

100
55.9

70.7

100
99.9

99.9

100
-

-

92.5
-

-

96
96.4

97.1

98
-

-

-
93.9

97.2

94
93.5

96.6

94
-

-

-
-

-

-
77.6

86.5

78
22.3

35.6

72
55.5

66.2

65
-

-

-
27.5

45

-
-

-

-
-

-

-
-

-

-
-

-

-
-

-

-
-

-

-
-

-

-
-

-

-
-

-

-

For a wider analysis go to PhosphoNET Evolution in PhosphoNET

Binding Proteins

Examples of known interacting proteins

hiddentext

No.	Name – UniProt ID
1	NTF4 - P34130
2	BDNF - P23560
3	NGFR - P08138
4	DOK5 - Q9P104
5	NCK2 - O43639
6	NCK1 - P16333
7	PIK3R1 - P27986
8	SHC2 - P98077
9	DYNLL1 - P63167
10	KIDINS220 - Q9ULH0
11	RPS27A - P62988
12	FRS2 - Q8WU20

Regulation

Activation:

Activated by binding BDNF, NT-3, NT-4 or NT-5 growth factor, which induces dimerization and autophosphorylation. Phosphorylation at Tyr-516 increases phosphotransferase activity and induces interaction with PLCg1.

Inhibition:

Synthesis:

Degradation:

Kinections Map

Click here to download a PPT of the image below

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

CDK5	Q00535	S479	SNDDDSASPLHHISN
TRKB	Q16620	Y516	PVIENPQYFGITNSQ	+
TRKB	Q16620	Y702	FGMSRDVYSTDYYRV	+
TRKB	Q16620	Y706	RDVYSTDYYRVGGHT	+
TRKB	Q16620	Y707	DVYSTDYYRVGGHTM	+
TRKB	Q16620	Y817	LAKASPVYLDILG__

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

Kv1.3	P22001	Y161	PSFDAILYYYQSGGR
Kv1.3	P22001	Y162	SFDAILYYYQSGGRI
Kv1.3	P22001	Y163	FDAILYYYQSGGRIR
Kv1.3	P22001	Y499	EGEEQSQYMHVGSCQ
PLCG1	P19174	Y1253	EGSFESRYQQPFEDF
PLCG1	P19174	Y783	EGRNPGFYVEANPMP	+
Shc3	Q92529	Y341	GDGSDHPYYNSIPSK	?
Shc3	Q92529	Y342	DGSDHPYYNSIPSKM	?
Shc3	Q92529	Y379	FAGKEQTYYQGRHLG
Shc3	Q92529	Y380	AGKEQTYYQGRHLGD
Shc3	P29353	Y406	RQGSSDIYSTPEGKL
Shc3	P29353	Y424	PTGEAPTYVNTQQIP
Tiam1	Q13009	Y829	PQPEEDIYELLYKEI
TrkB (NTRK2)	Q16620	Y516	PVIENPQYFGITNSQ	+
TrkB (NTRK2)	Q16620	Y702	FGMSRDVYSTDYYRV	+
TrkB (NTRK2)	Q16620	Y706	RDVYSTDYYRVGGHT	+
TrkB (NTRK2)	Q16620	Y707	DVYSTDYYRVGGHTM	+
TrkB (NTRK2)	Q16620	Y817	LAKASPVYLDILG__

Protein Kinase Specificity

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

Matrix Type:

Experimentally derived from alignment of 29 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

CHEMBL1684800	IC50 = 1 nM	52938983	1684800	21353571
Staurosporine	IC50 = 1 nM	5279		22014755
Crizotinib	IC50 = 2 nM	11626560	601719	21812414
BMS-754807	IC50 = 4.1 nM	24785538		19996272
Foretinib	Kd = 4.1 nM	42642645	1230609	22037378
SNS314	IC50 = 5 nM	16047143	514582	18678489
Hesperadin	Kd < 10 nM	10142586	514409	19035792
MK5108	IC50 = 13 nM	24748204		20053775
Lestaurtinib	Kd = 14 nM	126565		22037378
Ponatinib	IC50 = 15.1 nM	24826799		20513156
Nintedanib	Kd = 19 nM	9809715	502835	22037378
Aloisine A	IC50 < 25 nM	5326843	75680	22037377
Gö6976	IC50 < 25 nM	3501	302449	22037377
GSK-3 Inhibitor XIII	IC50 < 25 nM	6419766	359482	22037377
IDR E804	IC50 < 25 nM	6419764	1802727	22037377
Indirubin-3′-monoxime	IC50 < 25 nM	5326739		22037377
K-252a; Nocardiopsis sp.	IC50 < 25 nM	3813	281948	22037377
Bosutinib	IC50 = 27 nM	5328940	288441	19039322
GW2580	Kd = 36 nM	11617559	261849	18183025
Cdk1/2 Inhibitor III	IC50 > 50 nM	5330812	261720	22037377
Doramapimod	IC50 = 50 nM	156422	103667	22014550
Dovitinib	IC50 > 50 nM	57336746		22037377
GSK-3 Inhibitor IX	IC50 > 50 nM	5287844	409450	22037377
JAK3 Inhibitor VI	IC50 > 50 nM	16760524		22037377
PF-03814735	IC50 < 50 nM	49830590		20354118
SB218078	IC50 > 50 nM	447446	289422	22037377
SU11652	IC50 > 50 nM	24906267	13485	22037377
Syk Inhibitor	IC50 > 50 nM	6419747	104279	22037377
AT9283	IC50 > 100 nM	24905142		19143567
NVP-TAE684	Kd = 130 nM	16038120	509032	22037378
KW2449	Kd = 140 nM	11427553	1908397	22037378
BCP9000906	IC50 > 150 nM	5494425	21156	22037377
BML-275	IC50 > 150 nM	11524144	478629	22037377
PDK1/Akt/Flt Dual Pathway Inhibitor	IC50 > 150 nM	5113385	599894	22037377
PKR Inhibitor	IC50 > 150 nM	6490494	235641	22037377
Semaxinib	IC50 > 150 nM	5329098	276711	22037377
SU6656	IC50 > 150 nM	5353978	605003	22037377
AST-487	Kd = 190 nM	11409972	574738	18183025
BMS-777607	IC50 = 190 nM	24794418		19260711
Tozasertib	Kd = 240 nM	5494449	572878	18183025
Flt-3 Inhibitor II	IC50 > 250 nM	11601743	377193	22037377
GSK-3 Inhibitor X	IC50 > 250 nM	6538818	430226	22037377
IKK-2 Inhibitor IV	IC50 > 250 nM	9903786	257167	22037377
JNJ-7706621	IC50 > 250 nM	5330790	191003	22037377
Purvalanol A	IC50 > 250 nM	456214	23327	22037377
SU11274	IC50 > 250 nM	9549297	261641	22037377
SU9516	IC50 > 250 nM	5289419	258805	22037377
VEGFR2 Kinase Inhibitor II	IC50 > 250 nM	5329155	88606	22037377
N-Benzoylstaurosporine	Kd = 310 nM	56603681	608533	18183025
Ruxolitinib	Kd = 360 nM	25126798	1789941	22037378
Nilotinib	Kd = 490 nM	644241	255863	22037378
1;9-Pyrazoloanthrone	IC50 = 500 nM	8515	7064	22037377
AG-E-60384	IC50 = 500 nM	6419741	413188	22037377
CGP74514A	IC50 = 500 nM	2794188	367625	22037377
Flt-3 Inhibitor III	IC50 = 500 nM	11772958		22037377
NU6140	IC50 = 500 nM	10202471	1802728	22037377
SU4312	IC50 = 500 nM	6450842	328710	22037377
Sunitinib	Kd = 590 nM	5329102	535	18183025
Aurora A Inhibitor 23 (DF)	Kd < 600 nM			21992004
Quizartinib	Kd = 620 nM	24889392	576982	19654408
Tandutinib	Kd = 740 nM	3038522	124660	18183025
Momelotinib	IC50 < 750 nM	25062766		19295546
Aurora A Inhibitor 1 (DF)	Kd < 800 nM			21992004
PHA-665752	Kd = 800 nM	10461815	450786	22037378
SU14813	Kd = 990 nM	10138259	1721885	18183025
AGL2043	IC50 > 1 µM	9817165		22037377
ALX-270-403-M001	IC50 > 1 µM			22037377
Bisindolylmaleimide I	IC50 > 1 µM	2396	7463	22037377
Compound 52	IC50 > 1 µM	2856		22037377
CP673451	IC50 > 1 µM	10158940		15705896
GTP-14564	IC50 > 1 µM	3385203	406375	22037377
IRAK-1-4 Inhibitor I	IC50 > 1 µM	11983295	379787	22037377
Kinome_714	IC50 > 1 µM	46886323		20346655
PD98059	IC50 > 1 µM	4713	35482	22037377
PKR Inhibitor; Negative Control	IC50 > 1 µM	16760619		22037377
Silmitasertib	IC50 > 1 µM	24748573		21174434
ST078197	IC50 > 1 µM	1048845	210833	22037377
VEGFR2 Kinase Inhibitor I	IC50 > 1 µM	6419834	86943	22037377
WZ3146	Kd > 1 µM	44607360		20033049
WZ4002	Kd > 1 µM	44607530		20033049
Linifanib	Kd = 1.1 µM	11485656	223360	18183025
AC1NS4N8	Kd < 1.25 µM	5353854	101797	19035792
Sorafenib	Kd = 2.1 µM	216239	1336	18183025
TG101348	Kd = 3.1 µM	16722836	1287853	22037378
SureCN4875304	IC50 > 3.5 µM	46871765		20472445
JNJ-28871063	IC50 > 4 µM	17747413		17975007
JNK Inhibitor VIII	Ki = 4.5 µM	11624601	210618	16759099
Kinome_2553	Ki > 4.5 µM	16007116	377383	16854050
Kinome_3024	Ki > 4.5 µM	11539329	210963	16759099
Kinome_3027	Ki > 4.5 µM	11640926	378627	16759099
Kinome_3028	Ki > 4.5 µM	11590363	210928	16759099
CHEMBL248757	Ki > 4.536 µM	44444843	248757	17935989

Disease Linkage

General Disease Association:

Cancer, metabolic disorders

Specific Diseases (Non-cancerous):

Obesity; Obesity, Hyperphagia, and developmental delay (OHPDD)

Comments:

Obesity is considered a rare disease with regard to a genetic propensity. Obesity can arise from excessive weight in muscle, bone, fat, and or body water. Obesity, Hyperphagia, and Developmental Delay (OHPDD) is a condition characterized by obesity at a young age, increased appetite for food (hyperphagia), and a severe delay in the development of speech, language, and motor control. In OHPDD an Y706C mutation in the TRKB gene will inhibit phosphorylation.

Specific Cancer Types:

Pilocytic astrocytomas; Neuroblastomas (NB)

Comments:

TRKB is linked to Pilocytic Astrocytomas, which are benign tumours of the brain or spinal cord that grow slowly.

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: Barrett's esophagus epithelial metaplasia (%CFC= -48, p<0.002); Breast epithelial carcinomas (%CFC= -53, p<0.048); Clear cell renal cell carcinomas (cRCC) stage I (%CFC= -78, p<0.0006); Head and neck squamous cell carcinomas (HNSCC) (%CFC= +81, p<0.033); Lung adenocarcinomas (%CFC= -57, p<0.0001); Malignant pleural mesotheliomas (MPM) tumours (%CFC= -67, p<0.011); Pituitary adenomas (ACTH-secreting) (%CFC= -79, p<0.095); Skin melanomas - malignant (%CFC= -69, p<0.001); and Skin squamous cell carcinomas (%CFC= -52, p<0.032). The COSMIC website notes an up-regulated expression score for TRKB in diverse human cancers of 353, which is 0.8-fold of the average score of 462 for the human protein kinases. The down-regulated expression score of 1 for this protein kinase in human cancers was 98% lower than 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: 0.1 % in 25532 diverse cancer specimens. This rate is only 37 % higher 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: 0.48 % in 1093 large intestine cancers tested; 0.35 % in 805 skin cancers tested; 0.31 % in 589 stomach cancers tested; 0.3 % in 602 endometrium cancers tested; 0.24 % in 1943 lung cancers tested; 0.14 % in 1270 liver cancers tested; 0.1 % in 1488 breast cancers tested.

Frequency of Mutated Sites:

None > 5 in 20,678 cancer specimens

Comments:

Only 1 deletion, and no insertions or complex mutations are noted on the COSMIC website.

COSMIC Entry:

NTRK2

OMIM Entry:

600456

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:

N-GlcNAcylated:

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:

Kinections Map

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:

Specific Cancer Types:

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: