Details for: TM4SF5

Gene ID: 9032

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: TM4SF5

Ensembl ID: ENSG00000142484

Description: transmembrane 4 L six family member 5

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • intrahepatic cholangiocyte CL0002538
    CSI 8.61
    rCSI 20.66%
    PRS 88.41
  • type EC enteroendocrine cell CL0000577
    CSI 8.47
    rCSI 30.07%
    PRS 88.83
  • midzonal region hepatocyte CL0019028
    CSI 7.74
    rCSI 18.16%
    PRS 85.31
  • enteroendocrine cell of small intestine CL0009006
    CSI 5.69
    rCSI 12.53%
    PRS 91.13
  • stem cell CL0000034
    CSI 5.68
    rCSI 5.47%
    PRS 81.89
  • colon epithelial cell CL0011108
    CSI 5.43
    rCSI 5.68%
    PRS 84.37
  • enterocyte CL0000584
    CSI 5.41
    rCSI 8.73%
    PRS 84.41
  • intestine goblet cell CL0019031
    CSI 4.18
    rCSI 3.71%
    PRS 84.3
  • pancreatic epsilon cell CL0005019
    CSI 4.04
    rCSI 18.81%
    PRS 91.44
  • type L enteroendocrine cell CL0002279
    CSI 4.01
    rCSI 7.52%
    PRS 90.23
  • periportal region hepatocyte CL0019026
    CSI 3.84
    rCSI 14.92%
    PRS 84.76
  • colonocyte CL1000347
    CSI 3.81
    rCSI 5.46%
    PRS 85.96
  • enteroendocrine cell CL0000164
    CSI 3.11
    rCSI 4.25%
    PRS 85.8
  • small intestine goblet cell CL1000495
    CSI 3.07
    rCSI 6.73%
    PRS 90.29
  • mucous neck cell CL0000651
    CSI 3
    rCSI 4.32%
    PRS 90.85
  • goblet cell CL0000160
    CSI 2.92
    rCSI 2.76%
    PRS 84.88
  • brush cell CL0002204
    CSI 2.72
    rCSI 5.39%
    PRS 91.55
  • centrilobular region hepatocyte CL0019029
    CSI 2.5
    rCSI 6.53%
    PRS 83.77
  • M cell of gut CL0000682
    CSI 2.25
    rCSI 2.39%
    PRS 89.75
  • intestinal tuft cell CL0019032
    CSI 2.18
    rCSI 3.32%
    PRS 89.35
  • hepatocyte CL0000182
    CSI 2.15
    rCSI 3.85%
    PRS 86.02
  • intestinal epithelial cell CL0002563
    CSI 1.94
    rCSI 2.03%
    PRS 84.41
  • transit amplifying cell of colon CL0009011
    CSI 1.79
    rCSI 2.1%
    PRS 87.69
  • epithelial cell of proximal tubule CL0002306
    CSI 1.78
    rCSI 4.36%
    PRS 79.69
  • BEST4+ enteroycte CL4030026
    CSI 1.74
    rCSI 2.16%
    PRS 87.01
  • paneth cell CL0000510
    CSI 1.68
    rCSI 2.48%
    PRS 93.42
  • tuft cell of colon CL0009041
    CSI 1.57
    rCSI 3.67%
    PRS 90.22
  • foveolar cell of stomach CL0002179
    CSI 1.35
    rCSI 2.88%
    PRS 90.1
  • colon goblet cell CL0009039
    CSI 1.28
    rCSI 3.03%
    PRS 89.78
  • enterocyte of epithelium of small intestine CL1000334
    CSI 1.25
    rCSI 19.29%
    PRS 91.17
  • intestinal crypt stem cell of small intestine CL0009017
    CSI 1.25
    rCSI 3.36%
    PRS 89.75
  • P/D1 enteroendocrine cell CL0002268
    CSI 0.82
    rCSI 4.44%
    PRS 90.71
  • paneth cell of epithelium of small intestine CL1000343
    CSI 0.77
    rCSI 2.15%
    PRS 91.11
  • enteroendocrine cell of colon CL0009042
    CSI 0.48
    rCSI 2.23%
    PRS 90.76
  • paneth cell of colon CL0009009
    CSI 0.39
    rCSI 3.84%
    PRS 91.9

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary Transmembrane 4 L six family member 5, or [TM4SF5](/details-gene/9032), is a protein-coding gene located on chromosome 17p13.2. As a member of the tetraspanin family, this protein is localized to the plasma and lysosomal membranes where it plays a critical role in cellular signaling and metabolism. Functional annotations and experimental evidence indicate its involvement in sensing amino acids, specifically through [arginine binding (GO:0034618)](https://www.ebi.ac.uk/QuickGO/term/GO:0034618), to modulate mTORC1 signaling ([Link](https://doi.org/10.1016/j.cmet.2019.03.005)). Furthermore, [TM4SF5](/details-gene/9032) is implicated in cell cycle control, specifically the [regulation of G1/S transition (GO:2000045)](https://www.ebi.ac.uk/QuickGO/term/GO:2000045) ([Link](https://doi.org/10.1016/j.bbamcr.2010.04.001)). Its expression profile is highly specific, with the greatest significance observed in epithelial and endocrine cells of the digestive system, including [intrahepatic cholangiocytes](/details-cell/CL0002538) and various [hepatocytes](/details-cell/CL0019028), suggesting a key role in the physiology and pathology of the liver and gastrointestinal tract. It has also been identified as a tumor-associated antigen, particularly in liver cancer ([Link](https://doi.org/10.1016/s0378-1119(97)00633-1)). ## Cellular Roles and Expression Landscape The expression pattern of [TM4SF5](/details-gene/9032) strongly indicates a specialized function within the epithelial and endocrine lineages of the gastrointestinal system. **Overall**, the gene shows the highest significance in cells of the liver and intestines. It is a top marker for [intrahepatic cholangiocyte](/details-cell/CL0002538) (CSI: 8.61), the epithelial cells lining the bile ducts, as well as both [midzonal region hepatocytes](/details-cell/CL0019028) (CSI: 7.74) and [periportal region hepatocytes](/details-cell/CL0019026) (CSI: 3.84). This prominent expression in the liver suggests a fundamental role in bile production, metabolism, and detoxification processes. Beyond the liver, [TM4SF5](/details-gene/9032) is highly significant in various secretory and absorptive cells of the gut. These include multiple types of [enteroendocrine cells](/details-cell/CL0000164) such as [type EC enteroendocrine cell](/details-cell/CL0000577) (CSI: 8.47) and [type L enteroendocrine cell](/details-cell/CL0002279) (CSI: 4.01), which are responsible for hormone secretion in response to nutrients. Its high CSI in absorptive [enterocytes](/details-cell/CL0000584) and secretory [intestine goblet cells](/details-cell/CL0019031) further solidifies its association with digestive and metabolic homeostasis. The gene's significance in [stem cells](/details-cell/CL0000034) (CSI: 5.68) is consistent with its role in regulating cell cycle progression, which is crucial for the high turnover rate of the intestinal epithelium. ## Pathways and Molecular Function The molecular functions of [TM4SF5](/details-gene/9032) are tightly linked to its subcellular localization at the [plasma membrane (GO:0005886)](https://www.ebi.ac.uk/QuickGO/term/GO:0005886) and [lysosomal membrane (GO:0005765)](https://www.ebi.ac.uk/QuickGO/term/GO:0005765). Its activity as a nutrient sensor is central to its biological role. Research has shown that [TM4SF5](/details-gene/9032) directly senses arginine availability, a key signal for activating the mTORC1 pathway, which is a master regulator of cell growth, proliferation, and metabolism ([Link](https://doi.org/10.1016/j.cmet.2019.03.005)). This function is particularly relevant in the metabolically active cells where it is highly expressed, such as [hepatocytes](/details-cell/CL0019028) and [enteroendocrine cells](/details-cell/CL0000164), which must constantly monitor and respond to nutrient fluctuations. In addition to its metabolic role, [TM4SF5](/details-gene/9032) directly influences cell proliferation by regulating the G1/S phase transition of the cell cycle. This is reportedly achieved by promoting the cytosolic localization of the cyclin-dependent kinase inhibitor p27Kip1, thereby preventing its nuclear function in halting cell cycle progression ([Link](https://doi.org/10.1016/j.bbamcr.2010.04.001)). This mechanism connects nutrient sensing directly to the decision for a cell to divide, a critical process for tissue maintenance and a pathway often dysregulated in cancer. ## Research Directions Given that [TM4SF5](/details-gene/9032) is identified as a tumor-associated antigen and functions at the nexus of nutrient sensing and cell cycle control, its role in malignancy warrants significant investigation, particularly in cancers of the digestive system where it is most prominently expressed. ### Proposed Hypotheses 1. **Metabolic Dependency in Liver Cancer:** Overexpression of [TM4SF5](/details-gene/9032) in hepatocellular carcinoma or cholangiocarcinoma creates a metabolic dependency on extracellular arginine. This hypersensitizes cancer cells to arginine levels, making them vulnerable to arginine deprivation therapies, which would selectively inhibit mTORC1 signaling and proliferation in [TM4SF5](/details-gene/9032)-high tumors. 2. **Driver of Colorectal Cancer Progression:** In colorectal cancer, where [TM4SF5](/details-gene/9032) is highly expressed in [colon epithelial cells](/details-cell/CL0011108), its primary oncogenic function is to drive proliferation by binding and sequestering p27Kip1 in the cytoplasm. The level of cytosolic p27Kip1, relative to nuclear p27Kip1, could serve as a prognostic biomarker for tumor aggressiveness in patients. ### Suggested Experimental Approach To test the first hypothesis regarding metabolic dependency, one could utilize CRISPR-Cas9 to generate [TM4SF5](/details-gene/9032) knockout and overexpressing isogenic cell lines from hepatocellular carcinoma (e.g., Huh7) and cholangiocarcinoma (e.g., EGI-1) backgrounds. The proliferation, survival, and mTORC1 pathway activity (measured by phosphorylation of S6K and 4E-BP1) of these engineered cells would be compared to wild-type controls when cultured in media with varying arginine concentrations. A significant reduction in proliferation and mTORC1 signaling specifically in the [TM4SF5](/details-gene/9032)-overexpressing cells under low-arginine conditions would support the hypothesis. ### Therapeutic Potential As a transmembrane protein with high expression in certain tumors, [TM4SF5](/details-gene/9032) represents a promising therapeutic target. Its surface accessibility makes it suitable for targeting with monoclonal antibodies, antibody-drug conjugates (ADCs), or CAR-T cell therapies. The therapeutic strategy would focus on **inhibition** or targeted cell killing, as its function promotes cell growth and proliferation. However, its significant expression in healthy epithelial tissues of the liver and gut raises potential concerns for on-target, off-tumor toxicity, which would need to be carefully evaluated in preclinical models. Targeting [TM4SF5](/details-gene/9032) might be most effective in combination with therapies that exploit the metabolic vulnerabilities it creates, such as arginine-depleting enzymes.

Genular Protein ID: 1209041109

Symbol: T4S5_HUMAN

Name: Transmembrane 4 L6 family member 5

UniProtKB Accession Codes:

O14894 Q17RW9 Q6IB79

Database IDs:

ABCD 1 AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CTD 1 ChEBI 1 ChEMBL 1 ChiTaRS 1 DNASU 1 DisGeNET 1 EMBL 5 Ensembl 1 GO 5 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 1 KEGG 1 MANE-Select 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PIR 1 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 RefSeq 1 STRING 1 SignaLink 1 TCDB 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 neXtProt 1

Citations:

PubMed ID: 9479038

Title: Identification of a new tumour-associated antigen TM4SF5 and its expression in human cancer.

PubMed ID: 9479038

DOI: 10.1016/s0378-1119(97)00633-1

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 20399237

Title: TM4SF5 accelerates G1/S phase progression via cytosolic p27Kip1 expression and RhoA activity.

PubMed ID: 20399237

DOI: 10.1016/j.bbamcr.2010.04.001

PubMed ID: 30956113

Title: Transmembrane 4 L six family member 5 senses arginine for mTORC1 signaling.

PubMed ID: 30956113

DOI: 10.1016/j.cmet.2019.03.005

Sequence Information:

  • Length: 197
  • Mass: 20823
  • Checksum: 051AEB5ECCE1075C
  • Sequence:
    • MCTGKCARCV GLSLITLCLV CIVANALLLV PNGETSWTNT NHLSLQVWLM GGFIGGGLMV 
LCPGIAAVRA GGKGCCGAGC CGNRCRMLRS VFSSAFGVLG AIYCLSVSGA GLRNGPRCLM 
NGEWGYHFED TAGAYLLNRT LWDRCEAPPR VVPWNVTLFS LLVAASCLEI VLCGIQLVNA 
TIGVFCGDCR KKQDTPH