SLC6A14 Gene

SLC6A14 Gene

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">SLC6A14 Gene</th>
</tr>
<tr>
<td class="label">Amino Acid</td>
<td>Transport Efficiency</td>
</tr>
<tr>
<td class="label">Leucine</td>
<td>High</td>
</tr>
<tr>
<td class="label">Phenylalanine</td>
<td>High</td>
</tr>
<tr>
<td class="label">Tryptophan</td>
<td>High</td>
</tr>
<tr>
<td class="label">Glutamine</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Methionine</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Histidine</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Application</td>
<td>Strategy</td>
</tr>
<tr>
<td class="label">Breast cancer</td>
<td>Small molecule inhibitors</td>
</tr>
<tr>
<td class="label">Obesity</td>
<td>Antisense oligonucleotides</td>
</tr>
<tr>
<td class="label">Chemotherapy sensitization</td>
<td>siRNA/shRNA</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/inflammation" style="color:#ef9a9a">Inflammation</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">7 edges</a></td>
</tr>
</table>

SLC6A14 Gene

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">SLC6A14 Gene</th>
</tr>
<tr>
<td class="label">Amino Acid</td>
<td>Transport Efficiency</td>
</tr>
<tr>
<td class="label">Leucine</td>
<td>High</td>
</tr>
<tr>
<td class="label">Phenylalanine</td>
<td>High</td>
</tr>
<tr>
<td class="label">Tryptophan</td>
<td>High</td>
</tr>
<tr>
<td class="label">Glutamine</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Methionine</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Histidine</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Application</td>
<td>Strategy</td>
</tr>
<tr>
<td class="label">Breast cancer</td>
<td>Small molecule inhibitors</td>
</tr>
<tr>
<td class="label">Obesity</td>
<td>Antisense oligonucleotides</td>
</tr>
<tr>
<td class="label">Chemotherapy sensitization</td>
<td>siRNA/shRNA</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/inflammation" style="color:#ef9a9a">Inflammation</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">7 edges</a></td>
</tr>
</table>

SLC6A14 encodes the amino acid transporter ATB0,+ (also known as B0AT2), a sodium/chloride-dependent neutral amino acid transporter primarily expressed in epithelial tissues including intestine, lung, mammary gland, and brain. SLC6A14 plays a critical role in nutrient uptake, cancer cell metabolism, and has been implicated in obesity, breast cancer, and other metabolic disorders[@broer2019][@nakanishi2023].

The SLC6A14 locus is on chromosome 9q32 and encodes a 12-transmembrane-domain protein of approximately 629 amino acids. Unlike many SLC6 family members that transport specific neurotransmitters, SLC6A14 has broad substrate specificity for neutral amino acids including leucine, phenylalanine, tryptophan, and glutamine. This broad specificity makes it a major gateway for amino acid uptake in rapidly dividing cells, including cancer cells that have elevated metabolic demands.

Gene And Protein Architecture

SLC6A14 encodes a member of the SLC6 family with the characteristic 12-transmembrane-domain topology:

• N-terminal intracellular domain: Contains regulatory serine/threonine residues
• Transmembrane core: Forms the broad substrate-binding pocket
• Large extracellular loops: Contains glycosylation sites
• C-terminal intracellular tail: Contains potential PDZ-binding motif

Transport Mechanism

SLC6A14 operates as a sodium/chloride-coupled neutral amino acid symporter with broad substrate specificity:

Substrate Profile

Physiologic Role

Intestinal Absorption

In the intestine, SLC6A14 mediates uptake of neutral amino acids from dietary protein:

• Located on apical membrane of enterocytes
• Works alongside other amino acid transporters (SLC7A5/LAT1, SLC1A5/ASCT2)
• Important for essential amino acid uptake
• Contributes to whole-body amino acid homeostasis

Lung and Mammary Gland

• Lung: Expressed in alveolar epithelium, may contribute to surfactant amino acid metabolism
• Mammary gland: Highly expressed during lactation for milk protein synthesis

Brain Expression

In the brain, SLC6A14 expression is more limited:

• Detected in certain neuronal populations
• May contribute to amino acid homeostasis at the blood-brain barrier
• Potential role in neurotransmitter precursor uptake (tryptophan for serotonin, phenylalanine for catecholamines)

SLC6A14 In Disease

Cancer Biology

SLC6A14 is overexpressed in multiple cancer types and contributes to tumor growth:

Breast cancer: High SLC6A14 expression correlates with:

• Poorer prognosis
• Increased cell proliferation
• Resistance to chemotherapy
• Enhanced metastasis

• Supply of essential amino acids for protein synthesis
• Support of mTORC1 signaling
• Enhanced glutamine utilization
• Integration with lipid metabolism pathways[@sreekumar2021]

• Tumor cell proliferation
• Angiogenesis through VEGF regulation
• Metabolic reprogramming toward aerobic glycolysis

• Non-small cell lung cancer (NSCLC) growth
• Resistance to targeted therapies
• Glutamine addiction in certain subtypes

Obesity and Metabolic Disorders

SLC6A14 is implicated in obesity through multiple mechanisms[@karunakaran2020]:

• Amino acid sensing: Regulates mTORC1 signaling in response to amino acid levels
• Adipocyte function: Affects lipid accumulation and adipogenesis
• Appetite regulation: Influences amino acid availability for hypothalamic neuropeptide synthesis

Neurological Implications

While less studied in neurodegeneration:

• May contribute to amino acid homeostasis in specific brain regions
• Potential role in neurotransmitter precursor supply
• Could influence protein synthesis in neurons under stress

Clinical Genetics

Disease-Associated Variants

SLC6A14 variants have been associated with:

• Obesity susceptibility: Common variants near SLC6A14 associated with BMI
• Cancer risk: Expression quantitative trait loci (eQTLs) in tumor susceptibility
• Metabolic syndrome: Rare variants in extreme obesity cohorts

Therapeutic Target Potential

SLC6A14 inhibition is being explored for:

Structural Biology

SLC6 Family Comparison

SLC6A14 shares structural features with other SLC6 transporters:

• 12-transmembrane helix architecture
• S1 substrate-binding site with broad specificity
• Na+ and Cl- binding sites
• Dimer formation (functional)

Inhibitor Development

Efforts to develop SLC6A14 inhibitors include:

• Substrate analogs: α-methyl amino acids
• Competitive blockers: Benzylserine derivatives
• Allosteric modulators: Target S2 site

Biomarker Relevance

Cancer Biomarker

SLC6A14 expression serves as:

• Prognostic marker: High expression = poor outcome in breast cancer
• Predictive marker: Predicts response to certain chemotherapies
• Therapeutic target: Inhibitors under development

Metabolic Biomarker

• Obesity: SLC6A14 expression in adipose tissue correlates with BMI
• Diabetes: Potential role in insulin sensitivity
• Fasting state: Downregulated during prolonged fasting

Research Models

Animal Models

• SLC6A14 knockout mice: Viable, lean phenotype with reduced adiposity
• Conditional knockouts: Tissue-specific deletion reveals organ-specific functions
• Transgenic overexpression: Promotes obesity and tumor growth

In Vitro Systems

• Cancer cell lines: Breast, colorectal, lung cancer models
• Enterocytes: Intestinal absorption studies
• Adipocytes: Metabolic function studies

Therapeutic Development

Cancer Therapy

SLC6A14 is an attractive target because:

• Overexpressed in cancer cells vs. normal cells
• Supports multiple metabolic pathways
• Knockdown inhibits tumor growth

• Normal tissue expression may cause toxicity
• Compensation by other amino acid transporters
• Resistance mechanisms

Metabolic Disease

SLC6A14 inhibition could:

• Reduce food intake through amino acid sensing
• Increase lipolysis in adipocytes
• Improve insulin sensitivity
• Lower circulating amino acids

Summary

SLC6A14 encodes ATB0,+, a broad-specificity sodium/chloride-coupled neutral amino acid transporter with important roles in nutrient absorption, cancer metabolism, and metabolic disease. The gene is overexpressed in multiple cancer types, making it a potential therapeutic target, while genetic variants influence obesity susceptibility.

Key aspects for neurodegeneration research include:

Pathway & Interaction Diagram

Interactive diagram showing SLC6A14's key relationships in the SciDEX knowledge graph (7 connections shown).

See Also

• [Amino Acid Transporters](/mechanisms/amino-acid-transport)
• [Cancer Metabolism](/mechanisms/cancer-metabolism)
• [mTORC1 Signaling](/mechanisms/mtorc1-signaling)
• [Obesity](/diseases/obesity)
• [Breast Cancer](/diseases/breast-cancer)

External Links

• [NCBI Gene](https://www.ncbi.nlm.nih.gov/gene/6388)
• [OMIM](https://www.omim.org/entry/300389)
• [UniProt](https://www.uniprot.org/uniprot/Q9H0Y5)
• [Ensembl](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000257151)

Allen Brain Atlas

• [Human Brain Map - SLC6A14 Expression](https://human.brain-map.org/microarray/search/show?search_term=SLC6A14)
• [BrainSpan Transcriptome Atlas](https://brainspan.org/)

References