# NTRK1 Gene: Structure, Function, and Clinical Significance


## Key Takeaways

- *NTRK1* encodes the TrkA receptor tyrosine kinase, crucial for neuronal development and survival, but also a potent oncogene when aberrantly activated by gene fusions or activating mutations in various adult and pediatric malignancies.
- Genomic rearrangements creating *NTRK1* fusions, such as with *TPM3* or *CD74*, lead to constitutive kinase activity, driving tumorigenesis across diverse cancers including lung, thyroid, and colorectal carcinomas, as well as sarcomas.
- Germline loss-of-function mutations in *NTRK1* cause Congenital Insensitivity to Pain with Anhidrosis (CIPA), a rare disorder characterized by impaired sensory neuron development and function.
- Selective small-molecule inhibitors, larotrectinib and entrectinib, targeting the TrkA kinase domain, represent a significant advancement in precision oncology, offering tissue-agnostic treatment for *NTRK* fusion-positive solid tumors.
- Resistance to TRK inhibitors often arises from secondary on-target mutations within the *NTRK1* kinase domain, such as p.G595R, necessitating the development of next-generation inhibitors like selitrectinib.
- Molecular profiling techniques, including next-generation sequencing (NGS) panels and immunohistochemistry (IHC) for pan-Trk, are essential for identifying *NTRK1* alterations and guiding targeted therapy decisions.

---

## Executive Summary & Key Metadata

The *NTRK1* gene (Neurotrophic Receptor Tyrosine Kinase 1) encodes the high-affinity receptor for nerve growth factor (NGF), a member of the neurotrophin family of growth factors. This receptor, also known as tropomyosin receptor kinase A (TrkA), is a type I transmembrane protein with intrinsic tyrosine kinase activity. Beyond its canonical role in the development, maintenance, and plasticity of the nervous system, *NTRK1* has emerged as a critical oncogene. Genomic rearrangements that generate constitutively active fusion proteins, as well as somatic point mutations, drive tumorigenesis across a diverse spectrum of adult and pediatric malignancies. The clinical significance of *NTRK1* is underscored by the FDA approval of selective small-molecule inhibitors (larotrectinib and entrectinib) that target its kinase domain, marking a paradigm shift in tissue-agnostic oncology.

| **Attribute** | **Detail** |
| :--- | :--- |
| **HGNC Symbol** | NTRK1 |
| **UniProt Accession** | P04629 |
| **Representative PDB ID** | 4PXO (Kinase domain with inhibitor) |
| **Chromosomal Locus** | 1q23.1 (GRCh38: chr1:156,815,750-156,881,850) |
| **Primary Molecular Function** | Receptor tyrosine kinase; signal transduction for NGF; regulation of neuronal survival, differentiation, and synaptic plasticity |
| **Disease & Pathology Associations** | Congenital insensitivity to pain with anhidrosis (CIPA); various carcinomas (lung, thyroid, colorectal), sarcomas (infantile fibrosarcoma), and gliomas via gene fusions or activating mutations |

## 1. Genomic Locus, Chromosomal Organization & Isoforms

### 1.1 Chromosomal Location and Gene Structure

The *NTRK1* gene is located on the long (q) arm of chromosome 1 at cytogenetic band q23.1. In the GRCh38 reference genome assembly, the gene spans approximately 66 kilobases (kb) of genomic DNA, from base pair 156,815,750 to 156,881,850 on the forward strand. The genomic architecture is complex, comprising 17 canonical exons that are alternatively spliced to produce multiple transcript variants. The gene is oriented in a head-to-tail manner with its neighboring genes, with the 5' end positioned towards the centromere.

The core promoter region of *NTRK1* lacks a canonical TATA box but is rich in GC content, a feature common to constitutively expressed or developmentally regulated genes. This region contains multiple binding sites for the transcription factor Specificity Protein 1 (Sp1), which is essential for basal transcriptional activity. Additionally, the promoter harbors response elements for several other transcription factors, including:
- **AP-1 (Activator Protein-1)**: Mediates transcriptional responses to growth factors, cytokines, and stress signals.
- **CREB (cAMP response element-binding protein)**: Links transcriptional regulation to intracellular cAMP levels and calcium signaling.
- **NF-κB (Nuclear Factor kappa-light-chain-enhancer of activated B cells)**: Implicated in inflammatory and survival pathways.

### 1.2 Enhancer Elements and Chromatin Architecture

While the promoter drives basal expression, the tissue-specific and developmental regulation of *NTRK1* is governed by distal cis-regulatory elements. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) data from the ENCODE project and the Roadmap Epigenomics Consortium reveal several putative enhancer regions located both upstream and within intronic sequences. These enhancer regions are marked by histone modifications characteristic of active regulatory elements, such as H3K27ac (acetylation of lysine 27 on histone H3) and H3K4me1 (monomethylation of lysine 4 on histone H3). One particularly well-characterized enhancer is located in intron 1, which has been shown to bind the neuronal transcription factor Brn-3a (POU4F1), driving high-level expression in sensory neurons.

The chromatin architecture at the *NTRK1* locus is organized into a topologically associating domain (TAD) that insulates it from the regulatory influence of neighboring genes. Within this TAD, the promoter and enhancers interact through chromatin looping, a process mediated by the CCCTC-binding factor (CTCF) and cohesin complex. Disruption of this chromatin architecture, through genomic rearrangements, can lead to aberrant *NTRK1* expression, a mechanism observed in some cancers where enhancer hijacking occurs.

### 1.3 Alternative Splicing and Isoforms

Alternative splicing of the *NTRK1* pre-mRNA generates multiple transcript variants that encode distinct protein isoforms. The two most extensively studied isoforms are:

1.  **TrkA-I (NM_002529)**: This is the full-length, canonical receptor. It is predominantly expressed in the peripheral nervous system, particularly in sensory and sympathetic neurons. TrkA-I is the primary mediator of NGF signaling in these cells.
2.  **TrkA-II (NM_001012331)**: This isoform differs from TrkA-I by the inclusion of an 18-amino acid sequence encoded by exon 9. This insertion is located in the extracellular juxtamembrane region, just proximal to the transmembrane domain. TrkA-II is expressed in the central nervous system and exhibits differential signaling properties compared to TrkA-I. Specifically, the exon 9 insert has been shown to modulate receptor internalization and the activation of specific downstream pathways, such as the phosphatidylinositol 3-kinase (PI3K) pathway.

Additional, less abundant splice variants have been described, including:
- **TrkA-III**: A truncated isoform that lacks the extracellular ligand-binding domain and is constitutively active. It has been identified in neuroblastoma and is associated with a more aggressive tumor phenotype.
- **TrkA-S (short)**: A soluble isoform generated by intronic polyadenylation, which lacks the transmembrane and kinase domains. It may act as a dominant-negative regulator by sequestering NGF.

The regulation of alternative splicing is cell-type specific and developmentally controlled, adding a layer of functional complexity to the *NTRK1* locus.

## 2. 3D Protein Domain Architecture & Structural Biology

The TrkA protein is a single-pass type I transmembrane glycoprotein. Its mature form, following cleavage of the 32-amino acid signal peptide, is composed of 790 amino acids. The protein is organized into three principal domains: a large extracellular domain (ECD), a single hydrophobic transmembrane helix, and an intracellular region containing the tyrosine kinase domain.

### 2.1 Extracellular Domain (ECD)

The ECD (residues ~33-417) is responsible for ligand binding and receptor dimerization. It is composed of a unique arrangement of structural modules:
- **Leucine-Rich Repeat (LRR) Domain**: Flanked by two cysteine-rich clusters (LRR-N and LRR-C), this domain forms the core of the ligand-binding site. The LRR domain adopts a curved, solenoid structure that provides a large surface for protein-protein interactions.
- **Immunoglobulin-Like (Ig) Domains**: The ECD contains three Ig-like domains (Ig1, Ig2, and Ig3). The membrane-proximal Ig3 domain (also known as the C2-type Ig domain) is critical for NGF binding. Structural studies have demonstrated that NGF binds to a composite surface formed by the LRR domain and the Ig2 domain, while the Ig3 domain is involved in receptor dimerization and stabilization of the ligand-receptor complex.

The ECD is heavily glycosylated, with multiple N-linked glycosylation sites. These glycans are essential for proper protein folding, trafficking to the cell surface, and ligand binding affinity.

### 2.2 Transmembrane Domain

A single alpha-helical transmembrane domain (residues ~418-440) anchors the receptor to the plasma membrane. While primarily serving a structural role, the transmembrane domain can influence receptor dimerization and lateral mobility within the membrane.

### 2.3 Intracellular Tyrosine Kinase Domain

The intracellular region (residues ~441-790) contains the catalytic tyrosine kinase domain. This domain is the effector of TrkA signaling and the target of therapeutic inhibitors. The kinase domain adopts the canonical bilobed architecture of protein kinases:
- **N-terminal Lobe (N-lobe)**: Primarily composed of beta-sheets, this lobe contains the conserved glycine-rich loop (GxGxxG motif) that binds and positions ATP.
- **C-terminal Lobe (C-lobe)**: Predominantly alpha-helical, this lobe contains the catalytic loop (HRDLAARN) and the activation loop (A-loop).

The activation loop is a critical regulatory element. In the inactive state, the A-loop adopts a conformation that blocks the substrate-binding site. Upon ligand-induced receptor dimerization and autophosphorylation, specific tyrosine residues within the A-loop (primarily Tyr-791) are phosphorylated. This phosphorylation induces a conformational change that stabilizes the active, open conformation of the kinase domain, allowing for ATP and substrate binding.

Key functional residues and motifs within the kinase domain include:
- **Lys-544 (K544)**: Located in the N-lobe, this residue is essential for ATP binding and is a common site for inactivating mutations.
- **Tyr-676 (Y676)**: A major autophosphorylation site within the activation loop.
- **Tyr-680 (Y680)**: Another autophosphorylation site in the activation loop.
- **Tyr-681 (Y681)**: A third autophosphorylation site in the activation loop.
- **Tyr-496 (Y496)**: Located in the juxtamembrane region, this site is phosphorylated and serves as a docking site for the adaptor protein SHC (Src homology 2 domain containing) transforming protein 1.

### 2.4 Structural Basis of Ligand Binding and Activation

The binding of NGF to the TrkA ECD occurs with high affinity (Kd ~10⁻¹¹ M). The crystal structure of the NGF/TrkA complex reveals a 2:2 stoichiometry, where a single NGF homodimer binds to two TrkA receptor molecules. The binding interface is extensive and involves the LRR domain and the Ig2 domain of TrkA. This binding brings two TrkA receptors into close proximity, facilitating the trans-autophosphorylation of their intracellular kinase domains. The initial phosphorylation events occur on the activation loop tyrosines (Y676, Y680, Y681), which fully activates the kinase. Subsequent autophosphorylation on other tyrosine residues (Y496, Y751, Y785) creates docking sites for downstream signaling proteins.

[Interactive 3D Protein Visualizer: Load NTRK1 (PDB: true)](/tools/protein-structure-viewer?source=alphafold&accession=P04629)

## 3. Cellular Signaling Pathways & Molecular Function

TrkA is the primary signal transducer for NGF, mediating its diverse biological effects on neuronal survival, differentiation, neurite outgrowth, and synaptic plasticity. The signaling cascades initiated by TrkA are complex and tightly regulated, involving multiple downstream pathways.

### 3.1 The Canonical NGF/TrkA Signaling Axis

Upon NGF binding and receptor autophosphorylation, the intracellular phosphotyrosine residues serve as docking sites for adaptor proteins that link TrkA to downstream signaling cascades. The three major pathways activated are:

1.  **The RAS-MAPK (Mitogen-Activated Protein Kinase) Pathway**: This pathway is critical for neuronal differentiation and neurite outgrowth. The adaptor protein SHC binds to phosphorylated Y496 via its PTB (phosphotyrosine-binding) domain. SHC is then phosphorylated by TrkA, creating a binding site for the adaptor protein GRB2 (Growth factor receptor-bound protein 2). GRB2, in complex with the guanine nucleotide exchange factor SOS (Son of Sevenless), activates RAS by promoting the exchange of GDP for GTP. Active RAS initiates a kinase cascade involving RAF, MEK (MAPK/ERK kinase), and ERK (Extracellular signal-regulated kinase). Activated ERK translocates to the nucleus and phosphorylates transcription factors such as ELK-1 and CREB, regulating gene expression programs for differentiation.
2.  **The PI3K (Phosphoinositide 3-Kinase)-AKT Pathway**: This pathway is a major mediator of neuronal survival. TrkA activates PI3K through two distinct mechanisms: (a) direct binding of the p85 regulatory subunit of PI3K to phosphorylated Y751, and (b) indirect activation via the RAS pathway. PI3K generates the lipid second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP3), which recruits AKT to the plasma membrane, where it is phosphorylated and activated by PDK1 (Phosphoinositide-dependent kinase-1) and mTORC2 (mammalian target of rapamycin complex 2). Active AKT phosphorylates and inactivates pro-apoptotic proteins such as BAD and the Forkhead box O (FOXO) transcription factors, promoting cell survival.
3.  **The PLCγ-1 (Phospholipase C gamma-1) Pathway**: This pathway regulates intracellular calcium levels and the activity of protein kinase C (PKC). PLCγ-1 binds directly to phosphorylated Y785. Upon activation, PLCγ-1 hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to generate two second messengers: inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 triggers the release of calcium from intracellular stores, while DAG activates PKC. This pathway is involved in synaptic plasticity and the regulation of ion channel activity.

### 3.2 Receptor Trafficking and Signal Termination

The duration and intensity of TrkA signaling are tightly controlled by receptor trafficking and degradation. Upon ligand binding, TrkA is rapidly internalized via clathrin-mediated endocytosis. The internalized signaling endosomes can be transported retrogradely from the axon terminal to the cell body, a process essential for mediating the long-range survival signals of NGF. Within the endosome, TrkA can continue to signal, activating ERK5, which is crucial for neuronal survival.

Signal termination is achieved through several mechanisms:
- **Receptor Ubiquitination**: The E3 ubiquitin ligase NEDD4-2 (Neural precursor cell expressed developmentally down-regulated protein 4-2) binds to TrkA and catalyzes the attachment of ubiquitin chains, targeting the receptor for degradation in the lysosome.
- **Dephosphorylation**: Protein tyrosine phosphatases, such as PTP1B (Protein tyrosine phosphatase 1B) and SHP-2 (Src homology region 2 domain-containing phosphatase-2), can dephosphorylate TrkA, attenuating its kinase activity.
- **Endosomal Sorting**: Internalized receptors are sorted either for recycling back to the plasma membrane or for degradation in lysosomes, a decision that determines the overall signaling output.

### 3.3 Protein-Protein Interaction Networks

The signaling output of TrkA is determined by its dynamic interactions with a large network of proteins. Beyond the core adaptors (SHC, GRB2, PLCγ-1, PI3K), TrkA interacts with numerous other proteins that modulate its function. These include:
- **p75NTR (Neurotrophin Receptor p75)**: This low-affinity pan-neurotrophin receptor can form a complex with TrkA. The p75NTR/TrkA heterodimer increases the binding affinity of NGF and enhances the specificity of TrkA signaling. Conversely, in the absence of TrkA, p75NTR can signal independently to promote apoptosis.
- **KIDINS220 (Kinase D-interacting substrate of 220 kDa)**: A scaffold protein that binds to the juxtamembrane region of TrkA and is required for sustained MAPK signaling.
- **RIN2 (Ras and Rab interactor 2)**: A guanine nucleotide exchange factor for Rab5, a small GTPase involved in endosome fusion. RIN2 links TrkA to the endocytic machinery.
- **ARMS (Ankyrin repeat-rich membrane spanning protein, also known as Kidins220)**: Acts as a scaffold to coordinate the assembly of signaling complexes on TrkA.

```mermaid
sequenceDiagram
    participant NGF as "NGF Dimer"
    participant TrkA as "TrkA Receptor"
    participant SHC as "SHC Adaptor"
    participant GRB2 as "GRB2/SOS Complex"
    participant RAS as "RAS-GDP"
    participant RAF as "RAF Kinase"
    participant MEK as "MEK Kinase"
    participant ERK as "ERK Kinase"
    participant PI3K as "PI3K"
    participant AKT as "AKT Kinase"
    participant PLC as "PLCγ-1"
    participant IP3 as "IP3/DAG"
    NGF->>TrkA: Binds to ECD
    TrkA->>TrkA: Dimerization & Autophosphorylation (Y496, Y751, Y785)
    TrkA->>SHC: Binds pY496
    SHC->>GRB2: Recruits GRB2/SOS
    GRB2->>RAS: Promotes GTP/GDP exchange
    RAS->>RAF: Activates
    RAF->>MEK: Phosphorylates & Activates
    MEK->>ERK: Phosphorylates & Activates
    ERK-->>Nucleus: Translocates & Regulates Transcription
    TrkA->>PI3K: Binds pY751
    PI3K->>AKT: Generates PIP3, Recruits & Activates
    AKT-->>Cytoplasm: Promotes Survival
    TrkA->>PLC: Binds pY785
    PLC->>IP3: Generates IP3 & DAG
    IP3-->>ER: Releases Ca2+
```

## 4. Pathogenic Hotspot Mutations & Clinical Differentials

Alterations in *NTRK1* are associated with two distinct classes of human disease: rare congenital disorders and a wide array of cancers.

### 4.1 Germline Mutations in Congenital Insensitivity to Pain with Anhidrosis (CIPA)

CIPA, also known as Hereditary Sensory and Autonomic Neuropathy Type IV (HSAN IV), is a rare autosomal recessive disorder caused by loss-of-function mutations in *NTRK1*. Patients with CIPA present with insensitivity to pain and temperature, anhidrosis (inability to sweat), intellectual disability, and a propensity for self-mutilation. Over 100 distinct pathogenic mutations have been identified across the gene, including missense, nonsense, frameshift, and splice-site mutations. These mutations typically result in a complete loss of TrkA function, leading to the failure of NGF-dependent sensory and sympathetic neurons to develop and survive.

**ClinVar Pathogenic Variant Examples:**
- **c.1810C>T (p.Arg604Trp)**: A missense mutation in the kinase domain that disrupts ATP binding.
- **c.2217+1G>A**: A splice-site mutation that leads to aberrant mRNA splicing and a truncated protein.
- **c.851-2A>G**: A splice acceptor site mutation in intron 6, causing exon skipping and a frameshift.

### 4.2 Somatic Mutations and Gene Fusions in Cancer

In oncology, *NTRK1* is most prominently activated by genomic rearrangements that create fusion oncogenes. These fusions juxtapose the 3' region of *NTRK1*, encoding the kinase domain, with the 5' region of a variety of unrelated partner genes. The fusion partner typically provides a strong promoter and a dimerization domain, leading to constitutive, ligand-independent activation of the TrkA kinase. These fusions are potent oncogenic drivers and are found in a broad range of tumors, although they are rare overall (<1% of all solid tumors). However, they are highly prevalent in certain rare tumor types, such as infantile fibrosarcoma and secretory breast carcinoma, where they are present in over 90% of cases.

**Common *NTRK1* Fusion Partners:**
- **TPM3 (Tropomyosin 3)**: The most common fusion partner, frequently found in colorectal cancer, lung cancer, and soft tissue tumors.
- **LMNA (Lamin A/C)**: Found in soft tissue sarcomas and colorectal cancer.
- **CD74 (Cluster of Differentiation 74)**: Found in non-small cell lung cancer (NSCLC).
- **TFG (TRK-fused gene)**: Found in papillary thyroid carcinoma and NSCLC.
- **NFASC (Neurofascin)**: Found in glioblastoma.

**Somatic Point Mutations:** While less common than fusions, activating point mutations in *NTRK1* have also been identified in various cancers. These mutations are often located in the kinase domain and promote constitutive activation. Examples include:
- **p.G595R**: A mutation in the solvent-front region of the kinase domain, analogous to the T790M mutation in EGFR, which confers resistance to first-generation TRK inhibitors.
- **p.G667C**: A mutation in the xDFG motif that can also confer resistance to inhibitors.
- **p.V573M**: A mutation in the kinase domain that has been identified in lung cancer.

### 4.3 Clinical Differentials and Diagnosis

The diagnosis of *NTRK1*-altered cancers relies on molecular profiling techniques. Next-generation sequencing (NGS) panels that include targeted DNA and RNA sequencing are the most comprehensive approach, capable of detecting both point mutations and gene fusions. Immunohistochemistry (IHC) for pan-Trk is a highly sensitive screening method, but it can have false positives due to normal tissue expression. Fluorescence in situ hybridization (FISH) can be used to detect specific rearrangements. The identification of an *NTRK1* fusion is a critical clinical finding, as it directly informs the use of targeted therapy.

## 5. Host-Pathogen & Viral Interactions

The *NTRK1* gene product is not a primary target for viral oncoproteins in the same way as p53 or Rb. However, there are documented interactions between neurotrophic signaling and viral pathogenesis.

- **Herpes Simplex Virus (HSV) and Varicella-Zoster Virus (VZV)**: These neurotropic viruses establish latency in sensory neurons. NGF/TrkA signaling promotes the survival of these neurons and is required for the establishment and maintenance of latency. Conversely, the withdrawal of NGF can trigger viral reactivation. The viruses do not directly interact with TrkA, but they exploit the NGF signaling pathway to create a favorable cellular environment for persistence.
- **Human T-lymphotropic virus type 1 (HTLV-1)**: The HTLV-1 Tax oncoprotein has been shown to upregulate the expression of *NTRK1* in infected T-cells. This upregulation may contribute to the survival and proliferation of leukemic cells in Adult T-cell Leukemia/Lymphoma (ATLL), although the precise mechanism is not fully defined.
- **Oncolytic Viruses**: In the context of cancer therapy, the expression of TrkA on tumor cells is being explored as a target for oncolytic viral vectors engineered to bind to TrkA, thereby enhancing tumor-specific infection and lysis.

## 6. Pharmacogenomics, Drug Targets & Small-Molecule Inhibitors

The clinical success of TRK inhibitors has revolutionized the treatment of *NTRK* fusion-positive cancers. These drugs are the first examples of "tissue-agnostic" cancer therapies, approved based on the presence of a specific genetic alteration rather than the tumor's anatomical site of origin.

### 6.1 FDA-Approved Inhibitors

1.  **Larotrectinib (Vitrakvi)**: A highly selective, ATP-competitive inhibitor of the TRK family (TrkA, TrkB, TrkC). It was the first drug to receive FDA approval for the treatment of solid tumors with an *NTRK* gene fusion, regardless of tumor type. Clinical trials demonstrated an overall response rate of approximately 75% in adult and pediatric patients with *NTRK* fusion-positive cancers. Larotrectinib is administered orally.
2.  **Entrectinib (Rozlytrek)**: A multi-kinase inhibitor that targets TRK, ROS1, and ALK. It was also granted FDA approval for the treatment of *NTRK* fusion-positive solid tumors. In addition, it is approved for ROS1-positive non-small cell lung cancer. Entrectinib has excellent central nervous system (CNS) penetration, making it particularly effective for primary brain tumors and brain metastases.

### 6.2 Mechanisms of Resistance

Despite the remarkable initial efficacy of TRK inhibitors, acquired resistance inevitably develops in a majority of patients, typically within 1-2 years of treatment. The primary mechanisms of resistance are:

- **On-Target Mutations**: Secondary mutations in the *NTRK1* kinase domain that prevent drug binding. These are analogous to the T790M mutation in EGFR. Common resistance mutations include:
    - **Solvent-front mutations**: e.g., p.G595R, p.G667C.
    - **xDFG motif mutations**: e.g., p.G667C.
    - **Gatekeeper mutations**: e.g., p.F589L.
- **Off-Target Mechanisms**: Activation of bypass signaling pathways, such as the MET, EGFR, or IGF1R pathways, which can restore downstream signaling even when TrkA is inhibited.

### 6.3 Next-Generation Inhibitors

To overcome on-target resistance, next-generation TRK inhibitors are in clinical development. These agents are designed to be active against the common resistance mutations. Examples include:
- **Selitrectinib (LOXO-195)**: A next-generation inhibitor designed to bind to the kinase domain even in the presence of solvent-front mutations.
- **Repotrectinib (TPX-0005)**: A multi-kinase inhibitor that is potent against TRK, ROS1, and ALK, and has shown activity against TRK resistance mutations.

### 6.4 Pharmacogenomic Considerations

The response to TRK inhibitors is highly dependent on the presence of an *NTRK* gene fusion. The FDA approval of these drugs is linked to a companion diagnostic test that detects *NTRK* fusions. There are no established germline pharmacogenomic markers that predict response or toxicity to these agents, but ongoing research is exploring potential biomarkers.

## 7. Bioinformatic Resources & Database Accessions

The following table provides key database accessions and resources for the *NTRK1* gene and its protein product.

| **Database** | **Identifier / Accession** | **Description** |
| :--- | :--- | :--- |
| **NCBI Gene** | 4914 | Primary gene information, genomic context, and reference sequences. |
| **Ensembl** | ENSG00000198400 | Comprehensive genome annotation, transcripts, and variation data. |
| **UniProt** | P04629 | Protein sequence, function, post-translational modifications, and structure. |
| **RCSB PDB** | 4PXO, 2IFG, 1WWA | Experimentally determined 3D structures of the TrkA kinase domain and ECD. |
| **Gene Ontology (GO)** | GO:0005030 (NGF binding), GO:0004713 (protein tyrosine kinase activity), GO:0048013 (hepatocyte growth factor receptor signaling pathway) | Standardized terms for molecular function, biological process, and cellular component. |
| **ClinVar** | Gene: NTRK1 | Database of clinically relevant human variants and their pathogenicity. |
| **COSMIC** | Gene: NTRK1 | Catalogue of somatic mutations in cancer. |
| **STRING** | NTRK1 (P04629) | Protein-protein interaction networks. |
| **BioGRID** | NTRK1 | Curated protein and genetic interactions. |
| **The Human Protein Atlas** | ENSG00000198400 | Tissue and cell line expression data, and subcellular localization. |
| **OMIM** | 191315 | Mendelian Inheritance in Man: gene and phenotype relationships. |

## Related Clinical & Scientific Guides

* [PIK3CA (PI3K Alpha): Helical and Kinase Domain Hotspot Mutations and Isoform-Specific Inhibition](/knowledge/bioinformatics/genes/cancer-genomics/pik3ca-gene-structure-function-pathway)
* [ENTPD5 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/cancer-genomics/entpd5-gene-structure-function-pathway)
* [PDGFB Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/cancer-genomics/pdgfb-gene-structure-function-pathway)


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