TISIDB

Summary
Symbol	NTRK1
Name	neurotrophic tyrosine kinase, receptor, type 1
Aliases	TRKA; high affinity nerve growth factor receptor; Trk-A; p140-TrkA; Oncogene TRK; TRK1-transforming tyrosine ......
Chromosomal Location	1q21-q22
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Basic function annotation. > Subcellular Location, Domain and Function > Gene Ontology > KEGG and Reactome Pathway

> Subcellular Location, Domain and Function [ TOP ]
Subcellular Location	Cell membrane Single-pass type I membrane protein Early endosome membrane Single-pass type I membrane protein Late endosome membrane Single-pass type I membrane protein Note=Rapidly internalized after NGF binding (PubMed:1281417). Internalized to endosomes upon binding of NGF or NTF3 and further transported to the cell body via a retrograde axonal transport. Localized at cell membrane and early endosomes before nerve growth factor (NGF) stimulation. Recruited to late endosomes after NGF stimulation. Colocalized with RAPGEF2 at late endosomes.
Domain	PF13855 Leucine rich repeat PF07714 Protein tyrosine kinase PF16920 Tyrosine-protein kinase receptor C2 Ig-like domain
Function	Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympathetic and nervous neurons. High affinity receptor for NGF which is its primary ligand (PubMed:1850821, PubMed:1849459, PubMed:1281417, PubMed:8325889, PubMed:15488758, PubMed:17196528, PubMed:27445338). Can also bind and be activated by NTF3/neurotrophin-3. However, NTF3 only supports axonal extension through NTRK1 but has no effect on neuron survival (By similarity). Upon dimeric NGF ligand-binding, undergoes homodimerization, autophosphorylation and activation (PubMed:1281417). Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades driving cell survival and differentiation. Through SHC1 and FRS2 activates a GRB2-Ras-MAPK cascade that regulates cell differentiation and survival. Through PLCG1 controls NF-Kappa-B activation and the transcription of genes involved in cell survival. Through SHC1 and SH2B1 controls a Ras-PI3 kinase-AKT1 signaling cascade that is also regulating survival. In absence of ligand and activation, may promote cell death, making the survival of neurons dependent on trophic factors. ; FUNCTION: Isoform TrkA-III: Resistant to NGF, it constitutively activates AKT1 and NF-kappa-B and is unable to activate the Ras-MAPK signaling cascade. Antagonizes the anti-proliferative NGF-NTRK1 signaling that promotes neuronal precursors differentiation. Isoform TrkA-III promotes angiogenesis and has oncogenic activity when overexpressed.

> Gene Ontology [ TOP ]
Biological Process	GO:0000186 activation of MAPKK activity GO:0001101 response to acid chemical GO:0002064 epithelial cell development GO:0002521 leukocyte differentiation GO:0007018 microtubule-based movement GO:0007265 Ras protein signal transduction GO:0007270 neuron-neuron synaptic transmission GO:0007409 axonogenesis GO:0007411 axon guidance GO:0007416 synapse assembly GO:0007548 sex differentiation GO:0007568 aging GO:0007611 learning or memory GO:0007623 circadian rhythm GO:0007635 chemosensory behavior GO:0008406 gonad development GO:0008584 male gonad development GO:0009266 response to temperature stimulus GO:0009314 response to radiation GO:0009415 response to water GO:0009581 detection of external stimulus GO:0009582 detection of abiotic stimulus GO:0009612 response to mechanical stimulus GO:0009991 response to extracellular stimulus GO:0010035 response to inorganic substance GO:0010623 programmed cell death involved in cell development GO:0010720 positive regulation of cell development GO:0010975 regulation of neuron projection development GO:0010976 positive regulation of neuron projection development GO:0014823 response to activity GO:0016048 detection of temperature stimulus GO:0018108 peptidyl-tyrosine phosphorylation GO:0018212 peptidyl-tyrosine modification GO:0019233 sensory perception of pain GO:0021545 cranial nerve development GO:0021553 olfactory nerve development GO:0021675 nerve development GO:0030098 lymphocyte differentiation GO:0030183 B cell differentiation GO:0031346 positive regulation of cell projection organization GO:0031667 response to nutrient levels GO:0032147 activation of protein kinase activity GO:0033555 multicellular organismal response to stress GO:0033674 positive regulation of kinase activity GO:0035094 response to nicotine GO:0035249 synaptic transmission, glutamatergic GO:0038179 neurotrophin signaling pathway GO:0038180 nerve growth factor signaling pathway GO:0042113 B cell activation GO:0042490 mechanoreceptor differentiation GO:0042493 response to drug GO:0043279 response to alkaloid GO:0043405 regulation of MAP kinase activity GO:0043410 positive regulation of MAPK cascade GO:0043523 regulation of neuron apoptotic process GO:0043524 negative regulation of neuron apoptotic process GO:0044089 positive regulation of cellular component biogenesis GO:0044708 single-organism behavior GO:0045137 development of primary sexual characteristics GO:0045471 response to ethanol GO:0045666 positive regulation of neuron differentiation GO:0045860 positive regulation of protein kinase activity GO:0046546 development of primary male sexual characteristics GO:0046578 regulation of Ras protein signal transduction GO:0046579 positive regulation of Ras protein signal transduction GO:0046661 male sex differentiation GO:0046777 protein autophosphorylation GO:0048011 neurotrophin TRK receptor signaling pathway GO:0048013 ephrin receptor signaling pathway GO:0048015 phosphatidylinositol-mediated signaling GO:0048017 inositol lipid-mediated signaling GO:0048265 response to pain GO:0048266 behavioral response to pain GO:0048483 autonomic nervous system development GO:0048485 sympathetic nervous system development GO:0048511 rhythmic process GO:0048608 reproductive structure development GO:0048667 cell morphogenesis involved in neuron differentiation GO:0048678 response to axon injury GO:0050769 positive regulation of neurogenesis GO:0050803 regulation of synapse structure or activity GO:0050804 modulation of synaptic transmission GO:0050806 positive regulation of synaptic transmission GO:0050807 regulation of synapse organization GO:0050808 synapse organization GO:0050890 cognition GO:0050951 sensory perception of temperature stimulus GO:0050954 sensory perception of mechanical stimulus GO:0050961 detection of temperature stimulus involved in sensory perception GO:0050965 detection of temperature stimulus involved in sensory perception of pain GO:0050966 detection of mechanical stimulus involved in sensory perception of pain GO:0050974 detection of mechanical stimulus involved in sensory perception GO:0050982 detection of mechanical stimulus GO:0051056 regulation of small GTPase mediated signal transduction GO:0051057 positive regulation of small GTPase mediated signal transduction GO:0051090 regulation of sequence-specific DNA binding transcription factor activity GO:0051091 positive regulation of sequence-specific DNA binding transcription factor activity GO:0051092 positive regulation of NF-kappaB transcription factor activity GO:0051402 neuron apoptotic process GO:0051599 response to hydrostatic pressure GO:0051602 response to electrical stimulus GO:0051962 positive regulation of nervous system development GO:0051963 regulation of synapse assembly GO:0051965 positive regulation of synapse assembly GO:0051966 regulation of synaptic transmission, glutamatergic GO:0051968 positive regulation of synaptic transmission, glutamatergic GO:0060008 Sertoli cell differentiation GO:0060009 Sertoli cell development GO:0060384 innervation GO:0060385 axonogenesis involved in innervation GO:0061366 behavioral response to chemical pain GO:0061368 behavioral response to formalin induced pain GO:0061458 reproductive system development GO:0061564 axon development GO:0070371 ERK1 and ERK2 cascade GO:0070372 regulation of ERK1 and ERK2 cascade GO:0070374 positive regulation of ERK1 and ERK2 cascade GO:0070997 neuron death GO:0071312 cellular response to alkaloid GO:0071316 cellular response to nicotine GO:0071407 cellular response to organic cyclic compound GO:0071417 cellular response to organonitrogen compound GO:0071900 regulation of protein serine/threonine kinase activity GO:0097305 response to alcohol GO:0097485 neuron projection guidance GO:1901214 regulation of neuron death GO:1901215 negative regulation of neuron death GO:1990089 response to nerve growth factor GO:1990090 cellular response to nerve growth factor stimulus
Molecular Function	GO:0004713 protein tyrosine kinase activity GO:0004714 transmembrane receptor protein tyrosine kinase activity GO:0005003 ephrin receptor activity GO:0005004 GPI-linked ephrin receptor activity GO:0005030 neurotrophin receptor activity GO:0005126 cytokine receptor binding GO:0005165 neurotrophin receptor binding GO:0005166 neurotrophin p75 receptor binding GO:0010465 nerve growth factor receptor activity GO:0019199 transmembrane receptor protein kinase activity GO:0019838 growth factor binding GO:0043121 neurotrophin binding GO:0048406 nerve growth factor binding
Cellular Component	GO:0005769 early endosome GO:0005770 late endosome GO:0010008 endosome membrane GO:0030424 axon GO:0030425 dendrite GO:0031901 early endosome membrane GO:0031902 late endosome membrane GO:0043025 neuronal cell body GO:0043235 receptor complex GO:0044297 cell body GO:0044440 endosomal part

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa04010 MAPK signaling pathway hsa04144 Endocytosis hsa04210 Apoptosis hsa04722 Neurotrophin signaling pathway hsa04750 Inflammatory mediator regulation of TRP channels
Reactome	R-HSA-170984: ARMS-mediated activation R-HSA-187015: Activation of TRKA receptors R-HSA-170968: Frs2-mediated activation R-HSA-187037: NGF signalling via TRKA from the plasma membrane R-HSA-187024: NGF-independant TRKA activation R-HSA-198203: PI3K/AKT activation R-HSA-167021: PLC-gamma1 signalling R-HSA-169893: Prolonged ERK activation events R-HSA-177504: Retrograde neurotrophin signalling R-HSA-162582: Signal Transduction R-HSA-166520: Signalling by NGF R-HSA-187687: Signalling to ERKs R-HSA-167044: Signalling to RAS R-HSA-198745: Signalling to STAT3 R-HSA-187706: Signalling to p38 via RIT and RIN R-HSA-187042: TRKA activation by NGF

> KEGG and Reactome Pathway

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KEGG

hsa04010 MAPK signaling pathway
hsa04144 Endocytosis
hsa04210 Apoptosis
hsa04722 Neurotrophin signaling pathway
hsa04750 Inflammatory mediator regulation of TRP channels

Reactome

R-HSA-170984: ARMS-mediated activation
R-HSA-187015: Activation of TRKA receptors
R-HSA-170968: Frs2-mediated activation
R-HSA-187037: NGF signalling via TRKA from the plasma membrane
R-HSA-187024: NGF-independant TRKA activation
R-HSA-198203: PI3K/AKT activation
R-HSA-167021: PLC-gamma1 signalling
R-HSA-169893: Prolonged ERK activation events
R-HSA-177504: Retrograde neurotrophin signalling
R-HSA-162582: Signal Transduction
R-HSA-166520: Signalling by NGF
R-HSA-187687: Signalling to ERKs
R-HSA-167044: Signalling to RAS
R-HSA-198745: Signalling to STAT3
R-HSA-187706: Signalling to p38 via RIT and RIN
R-HSA-187042: TRKA activation by NGF

Summary
Symbol	NTRK1
Name	neurotrophic tyrosine kinase, receptor, type 1
Aliases	TRKA; high affinity nerve growth factor receptor; Trk-A; p140-TrkA; Oncogene TRK; TRK1-transforming tyrosine ......
Chromosomal Location	1q21-q22
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between NTRK1 and anti-tumor immunity. The specific mechanism were also collected if the literature reports that a gene specifically promotes or inhibits the infiltration or function of T/NK cells.

> Text Mining

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Literatures describing the relation between NTRK1 and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
23400852	Neuroblastoma	Promote immunity (T cell function)	Corresponding to this upregulation, T cell activity and cytoxicity was enhanced in the presence of SY5Y-TrkA cells or by medium conditioned by them, suggesting the existence of additional soluble factors stimulating the T cell response. Activation of natural killer (NK) cells was only increased in the presence of SY5Y-TrkA conditioned medium (CM) and not in co-culture assays, suggesting a dominant inhibitory effect of upregulated MHC class I as the primary NK cell escape mechanism of TrkA-expressing neuroblastomas.

Summary
Symbol	NTRK1
Name	neurotrophic tyrosine kinase, receptor, type 1
Aliases	TRKA; high affinity nerve growth factor receptor; Trk-A; p140-TrkA; Oncogene TRK; TRK1-transforming tyrosine ......
Chromosomal Location	1q21-q22
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	High-throughput screening data (e.g. CRISPR-Cas9, shRNA and RNAi) for T cell-mediated killing. Genetic screen techniques can identify mechanisms of tumor cell resistance (e.g., PTPN2) and sensitivity (e.g., APLNR) to killing by cytotoxic T cells, the central effectors of anti-tumor immunity. After comprehensively searching, eight groups of screening data sets were collected in the current database. In this tab, users can check whether their selected genes cause resistance or increase sensitivity to T cell-mediated killing in various data sets.

> High-throughput Screening

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Statistical results of NTRK1 in screening data sets for detecting immune reponses.

PMID	Screening System	Cancer Type	Cell Line	Data Set	Statistical Results	Relation to immunity
29301958	CRISPR-Cas9	melanoma	B16F10	Pmel-1 T cell	NA/NS	NA/NS
29301958	CRISPR-Cas9	melanoma	B16F10	OT-1 T cell	NA/NS	NA/NS
28783722	CRISPR-Cas9	melanoma	Mel624	2CT-CRISPR	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX+Anti-PD1	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX	NA/NS	NA/NS
25691366	RNAi	Breast cancer	MCF7	Luc-CTL assay	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Primary screen	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Secondary screen	NA/NS	NA/NS

Summary
Symbol	NTRK1
Name	neurotrophic tyrosine kinase, receptor, type 1
Aliases	TRKA; high affinity nerve growth factor receptor; Trk-A; p140-TrkA; Oncogene TRK; TRK1-transforming tyrosine ......
Chromosomal Location	1q21-q22
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Transcriptomic and genomic profiling of pre-treated tumor biopsies from responders and non-responders to immunotherapy. These data were used to identify signatures and mechanisms of response to checkpoint blockade (e.g., anti-PDL1 and anti-PD1). One example is that mutations in the gene PBRM1 benefit clinical survival of patients with clear cell renal cell carcinoma. After comprehensively searching, we collected 5 and 6 of transcriptomic and genomic data sets, respectively. In this tab, users can check whether their selected genes have significant difference of expression or mutation between responders and non-responders in various data sets. > Expression difference between responders and non-responders > Mutation difference between responders and non-responders

> Expression difference between responders and non-responders

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Points in the above scatter plot represent the expression difference of NTRK1 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	Log2 (Fold Change)	P value
1	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	14	12	-0.535	0.0908
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	-0.798	0.138
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	-0.35	0.447
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	-0.224	0.71
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0.005	0.997
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	-0.505	0.745
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	0.174	0.717
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	0.419	0.621
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	-0.091	0.92
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	0.148	0.758
11	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	2	0	0	1
12	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	2	8	0.077	0.907
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	-0.193	0.406

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of NTRK1 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	% Mut/Res	% Mut/NRes	% Diff (R vs NR)	Pval
1	25765070	Non-small cell lung cancer (NSCLC)	all	Anti-PD-1 (pembrolizumab)	14	17	7.1	5.9	1.2	1
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	0	0	0	1
3	25765070	Non-small cell lung cancer (NSCLC)	non-smoking	Anti-PD-1 (pembrolizumab)	4	14	25	7.1	17.9	0.405
4	26359337	Melanoma	all	Anti-CTLA-4 (ipilimumab)	27	73	11.1	4.1	7	0.339
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	0	0	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	11.1	5.1	6	0.373
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	0	11.8	-11.8	0.193
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	0	0	0	1
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	0	18.2	-18.2	0.199
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	11.1	6.2	4.9	1
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0	11.1	-11.1	1
12	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	25	0	25	0.364
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	5.3	7.4	-2.1	1
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	4.5	7.7	-3.2	1
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	6.2	7.1	-0.9	1
16	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	11	13	0	0	0	1
17	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	6	1	0	0	0	1
18	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	5	12	0	0	0	1

Summary
Symbol	NTRK1
Name	neurotrophic tyrosine kinase, receptor, type 1
Aliases	TRKA; high affinity nerve growth factor receptor; Trk-A; p140-TrkA; Oncogene TRK; TRK1-transforming tyrosine ......
Chromosomal Location	1q21-q22
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of NTRK1. The immune-related signatures of 28 TIL types from Charoentong's study, which can be viewed in the download page. For each cancer type, the relative abundance of TILs were inferred by using gene set variation analysis (GSVA) based on gene expression profile. In this tab, users can examine which kinds of TILs might be regulated by the current gene.

> Lymphocyte [ TOP ]

Summary
Symbol	NTRK1
Name	neurotrophic tyrosine kinase, receptor, type 1
Aliases	TRKA; high affinity nerve growth factor receptor; Trk-A; p140-TrkA; Oncogene TRK; TRK1-transforming tyrosine ......
Chromosomal Location	1q21-q22
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of NTRK1. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by NTRK1. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	NTRK1
Name	neurotrophic tyrosine kinase, receptor, type 1
Aliases	TRKA; high affinity nerve growth factor receptor; Trk-A; p140-TrkA; Oncogene TRK; TRK1-transforming tyrosine ......
Chromosomal Location	1q21-q22
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of NTRK1. In this tab, users can examine which chemokines (or receptors) might be regulated by the current gene. > Chemokine > Receptor

> Chemokine [ TOP ]

> Receptor [ TOP ]

Summary
Symbol	NTRK1
Name	neurotrophic tyrosine kinase, receptor, type 1
Aliases	TRKA; high affinity nerve growth factor receptor; Trk-A; p140-TrkA; Oncogene TRK; TRK1-transforming tyrosine ......
Chromosomal Location	1q21-q22
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of NTRK1 expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	NTRK1
Name	neurotrophic tyrosine kinase, receptor, type 1
Aliases	TRKA; high affinity nerve growth factor receptor; Trk-A; p140-TrkA; Oncogene TRK; TRK1-transforming tyrosine ......
Chromosomal Location	1q21-q22
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between NTRK1 and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	NTRK1
Name	neurotrophic tyrosine kinase, receptor, type 1
Aliases	TRKA; high affinity nerve growth factor receptor; Trk-A; p140-TrkA; Oncogene TRK; TRK1-transforming tyrosine ......
Chromosomal Location	1q21-q22
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting NTRK1 collected from DrugBank database.

> Drugs from DrugBank database

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Details on drugs targeting NTRK1.

ID	Name	Drug Type	Targets	#Targets
DB00321	Amitriptyline	Small Molecule	ADRA1A, ADRA1B, ADRA1D, ADRA2A, ADRB1, ADRB2, ADRB3, CHRM1, CHRM2, ......	35
DB00619	Imatinib	Small Molecule	ABL1, CSF1R, DDR1, KIT, NTRK1, PDGFRA, PDGFRB	7
DB08896	Regorafenib	Small Molecule	ABL1, BRAF, DDR2, EPHA2, FGFR1, FGFR2, FLT1, FLT4, FRK, KDR, KIT, ......	18

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