NPRL2 (NPR2-Like, GATOR1 Complex Subunit): A Tumor Suppressor and mTORC1 Regulator
Explore NPRL2 gene function, its role in cancer and epilepsy, expression data, mutations, and clinical significance.
Gene Information Card
| Symbol | NPRL2 |
|---|---|
| Full Name | NPR2-like, GATOR1 complex subunit |
| Gene Type | protein coding |
| Chromosomal Location | 3p21.31 |
| NCBI Gene ID | 29979 ncbi.nlm.nih.gov/gene/29979 |
| Ensembl ID | ENSG00000114315 |
| UniProt ID | Q8WTW4 |
| OMIM ID | 607072 |
| HGNC ID | 24969 |
| Aliases | TUS4, NPR2L, GATOR1 complex subunit NPRL2 |
Description
NPRL2 (NPR2-like, GATOR1 complex subunit) is a protein-coding gene located on chromosome 3p21.31. It encodes a component of the GATOR1 complex, which negatively regulates the mTORC1 signaling pathway in response to amino acid availability. NPRL2 functions as a tumor suppressor, and its loss or mutation has been implicated in various cancers and in familial focal epilepsy. The gene is also known as TUS4 (tumor suppressor 4) and NPR2L.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Cancer (multiple types) | Loss of NPRL2 expression or function leads to hyperactivation of mTORC1, promoting cell growth and proliferation. | COSMIC; multiple studies (e.g., lung, kidney, liver cancers) show reduced expression or mutations. |
| Familial focal epilepsy with variable foci (FFEVF) | Heterozygous mutations in NPRL2 cause dysregulation of GATOR1, leading to mTORC1 hyperactivation and neuronal hyperexcitability. | ClinVar; OMIM 607072; multiple case reports. |
| Focal cortical dysplasia (FCD) | Somatic mutations in NPRL2 in brain tissue lead to mTORC1 overactivation, causing cortical malformations and epilepsy. | ClinVar; literature. |
| Renal cell carcinoma | NPRL2 is located in a chromosomal region frequently deleted in renal cancer; loss of function contributes to tumorigenesis. | COSMIC; NCBI Gene. |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Lung | 12.4 | Medium |
| Kidney | 10.2 | Medium |
| Liver | 8.5 | Low |
| Brain | 7.8 | Low |
| Testis | 15.3 | High |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| A549 (Lung) | 14.2 | Moderate expression |
| HEK293 (Embryonic kidney) | 11.5 | Moderate |
| HepG2 (Liver) | 9.8 | Low |
| SH-SY5Y (Neuroblastoma) | 8.1 | Low |
| MCF7 (Breast) | 7.5 | Low |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.460C>T (p.Arg154*) | Nonsense | Rare | Loss of function; truncates protein, likely leading to nonsense-mediated decay. |
| c.77A>G (p.Gln26Arg) | Missense | Rare | Loss of function; impairs GATOR1 complex formation. |
| c.1015C>T (p.Arg339Trp) | Missense | Rare | Loss of function; disrupts protein stability. |
| c.1180_1181del (p.Leu394Valfs*3) | Frameshift | Rare | Loss of function; premature stop codon. |
| c.1A>G (p.Met1?) | Start codon loss | Rare | Loss of function; prevents translation initiation. |
Mutation functional classification
Loss of Function (LOF)
Most NPRL2 mutations are loss-of-function, leading to reduced or absent protein activity, resulting in mTORC1 hyperactivation.
Gain of Function (GOF)
No gain-of-function mutations have been reported for NPRL2.
Dominant Negative (DN)
Some missense mutations may exert a dominant-negative effect by disrupting the GATOR1 complex, but evidence is limited.
View complete mutation data：
Gene Ontology (GO)
| • GATOR1 complex | • GTPase activator activity |
| • negative regulation of TORC1 signaling | • regulation of cell growth |
| • cellular response to amino acid starvation | • signal transduction |
Pathways
• mTORC1 signaling
• Amino acid sensing
• GATOR1 complex pathway
Protein Summary
The NPRL2 protein is a subunit of the GATOR1 complex, which also includes DEPDC5 and NPRL3. GATOR1 acts as a GTPase-activating protein (GAP) for RagA/B, inhibiting mTORC1 signaling when amino acids are scarce. NPRL2 is essential for the stability and function of the complex. Loss of NPRL2 leads to constitutive mTORC1 activation, promoting cell growth and division. The protein is widely expressed, with higher levels in testis and lung. Its tumor suppressor role is supported by frequent downregulation in cancers and by the fact that its re-expression inhibits tumor growth.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| NPRL2 Knockout HEK293 Cell Line | EDJ-KQ1164 | Human | 10641 | Details Get a Quote |
| NPRL2 Knockout A-549 Cell Line | EDJ-KQ20415 | Human | 10641 | Details Get a Quote |
| NPRL2 Knockout HCT 116 Cell Line | EDJ-KQ20416 | Human | 10641 | Details Get a Quote |
| NPRL2 Knockout HeLa Cell Line | EDJ-KQ20417 | Human | 10641 | Details Get a Quote |
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