Details for: HAS3

Gene ID: 3038

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: HAS3

Ensembl ID: ENSG00000103044

Description: hyaluronan synthase 3

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • chondrocyte CL0000138
    CSI 14.58
    rCSI 23.2%
    PRS 97
  • stem cell CL0000034
    CSI 9.76
    rCSI 9.41%
    PRS 98.02
  • pericyte CL0000669
    CSI 9.39
    rCSI 25%
    PRS 85.95
  • epithelial cell of lung CL0000082
    CSI 6.53
    rCSI 5.41%
    PRS 99.07
  • basal-myoepithelial cell of mammary gland CL0002324
    CSI 5.05
    rCSI 9.55%
    PRS 99.28
  • basal cell of prostate epithelium CL0002341
    CSI 4.33
    rCSI 12.52%
    PRS 98.67
  • basal cell CL0000646
    CSI 4.16
    rCSI 5.56%
    PRS 97.52
  • club cell CL0000158
    CSI 3.49
    rCSI 5.11%
    PRS 97.82
  • respiratory basal cell CL0002633
    CSI 3.34
    rCSI 3.46%
    PRS 98.7
  • keratinocyte CL0000312
    CSI 3.11
    rCSI 2.6%
    PRS 97.73
  • respiratory suprabasal cell CL4033048
    CSI 2.73
    rCSI 3.5%
    PRS 98.83
  • suprabasal keratinocyte CL4033013
    CSI 2.69
    rCSI 4.4%
    PRS 84.76
  • basal cell of epidermis CL0002187
    CSI 2.4
    rCSI 4.25%
    PRS 82.99
  • enterocyte CL0000584
    CSI 2.37
    rCSI 3.83%
    PRS 96.95
  • melanocyte of skin CL1000458
    CSI 1.47
    rCSI 2.01%
    PRS 84.06
  • epithelial cell of urethra CL1000296
    CSI 0.35
    rCSI 8.79%
    PRS 98.61

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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  • 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 [HAS3](/details-gene/3038), or Hyaluronan Synthase 3, is a protein-coding gene located on chromosome 16q22.1. It encodes a multi-pass membrane enzyme that is central to the biosynthesis of hyaluronan (HA), a major glycosaminoglycan and a critical component of the extracellular matrix (ECM). The expression profile of [HAS3](/details-gene/3038) is most significant in cell types responsible for generating and maintaining connective and structural tissues, with particularly high expression in [chondrocyte](/details-cell/CL0000138)s. Its prevalence in [stem cell](/details-cell/CL0000034)s, [pericyte](/details-cell/CL0000669)s, and various basal and epithelial cell populations highlights its fundamental role in tissue architecture, hydration, repair, and cellular signaling. A clinical association for this gene is noted in OMIM ([602428](https://omim.org/entry/602428)). ## Cellular Roles and Expression Landscape The cellular expression pattern of [HAS3](/details-gene/3038) strongly reflects its primary function in ECM production and tissue maintenance. **Overall**, the gene exhibits its highest significance in [chondrocyte](/details-cell/CL0000138)s (CSI: 14.58), a finding consistent with the high abundance of hyaluronan required for the structural integrity and compressive resistance of cartilage. High significance is also observed in cell populations associated with tissue development, repair, and structural support. This includes [stem cell](/details-cell/CL0000034)s (CSI: 9.76) and [pericyte](/details-cell/CL0000669)s (CSI: 9.39), suggesting a role for [HAS3](/details-gene/3038) in morphogenesis, angiogenesis, and maintaining the microenvironment of stem cell niches. Furthermore, [HAS3](/details-gene/3038) is a notable marker across a wide range of epithelial and basal cells, including those of the lung ([epithelial cell of lung](/details-cell/CL0000082)), skin ([keratinocyte](/details-cell/CL0000312), [basal cell of epidermis](/details-cell/CL0002187)), and prostate ([basal cell of prostate epithelium](/details-cell/CL0002341)). This broad epithelial expression pattern suggests a conserved role in maintaining the integrity and function of barrier tissues throughout the body. ## Pathways and Molecular Function The function of [HAS3](/details-gene/3038) is centrally defined by its [hyaluronan synthase activity](/details-go/GO:0050501), as first characterized by molecular cloning studies ([Link](https://pubmed.ncbi.nlm.nih.gov/9083017/)). It catalyzes the synthesis of hyaluronan from UDP-glucuronic acid and UDP-N-acetylglucosamine. This activity is a core component of the [hyaluronan biosynthetic process](/details-go/GO:0030213) and is integral to [extracellular matrix assembly](/details-go/GO:0085029), as detailed in Reactome pathways such as [Hyaluronan biosynthesis and export](/details-pathway/R-HSA-2142850). Functionally, [HAS3](/details-gene/3038) is localized to the [plasma membrane](/details-go/GO:0005886) and [Golgi membrane](/details-go/GO:0000139), where it synthesizes and extrudes the growing hyaluronan polysaccharide chain directly into the extracellular space. Studies indicate that HAS enzymes, including [HAS3](/details-gene/3038), can form functionally relevant homo- and heteromeric complexes, which may provide a mechanism for regulating the rate of HA synthesis and the size of the resulting polymer ([Link](https://doi.org/10.1074/jbc.m115.640581)). While its primary role is enzymatic, functional annotations also suggest potential involvement in the [nucleus](/details-go/GO:0005634) and [positive regulation of dna-templated transcription](/details-go/GO:0045893), hinting at possible non-canonical roles or downstream signaling effects of its product that could influence gene expression. ## Research Directions Available evidence points towards a role for [HAS3](/details-gene/3038) beyond normal tissue homeostasis, particularly in pathology such as cancer. Its documented ability to promote prostate cancer cell growth ([Link](https://pubmed.ncbi.nlm.nih.gov/11431361/)) and its correlation with melanoma progression ([Link](https://doi.org/10.1007/s00018-016-2158-5)) suggest that dysregulation of [HAS3](/details-gene/3038) expression can contribute to disease. Based on these findings, several testable hypotheses can be proposed: 1. **Hypothesis 1 (Oncogenic Driver):** Upregulation of [HAS3](/details-gene/3038) in epithelial cancers is an active driver of malignant progression. By altering the physical properties and signaling capacity of the tumor microenvironment, increased hyaluronan production facilitates tumor cell proliferation, invasion, and immune evasion. 2. **Hypothesis 2 (Fibrosis and Regeneration):** In response to chronic tissue injury, such as in the lung or liver, sustained upregulation of [HAS3](/details-gene/3038) in stromal and progenitor cells is a key determinant that shifts the balance from orderly tissue regeneration toward pathological fibrosis by promoting excessive ECM deposition. A key experiment to test the first hypothesis would involve dissecting the direct contribution of [HAS3](/details-gene/3038) to cancer cell malignancy. Using a prostate cancer cell line (e.g., TSU) where its role has been previously implicated, one could employ CRISPR-Cas9 to generate a stable [HAS3](/details-gene/3038) knockout line and a non-targeting control. The functional consequences could then be assessed by comparing the proliferative, migratory, and invasive capabilities of the knockout and control cells *in vitro* using assays such as real-time cell analysis and Matrigel invasion assays. Subsequently, an orthotopic mouse xenograft model could be used to determine if the loss of [HAS3](/details-gene/3038) impairs tumor growth and metastasis *in vivo*. Given its role in promoting cancer progression, [HAS3](/details-gene/3038) represents a potential therapeutic target. The therapeutic strategy would focus on **inhibition** of its enzymatic activity. Development of specific small molecule inhibitors targeting [HAS3](/details-gene/3038) could serve to remodel the tumor microenvironment, potentially sensitizing tumors to other therapies like chemotherapy or immunotherapy. However, a significant challenge would be mitigating on-target, off-tumor effects, as hyaluronan is essential for many normal physiological processes. Therefore, targeted drug delivery systems or inhibitors with a high degree of selectivity may be required for clinical translation.

Genular Protein ID: 4257301785

Symbol: HYAS3_HUMAN

Name: Hyaluronan synthase 3

UniProtKB Accession Codes:

O00219 A8K5T5 Q8WTZ0 Q9NYP0

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CAZy 1 CCDS 2 CDD 1 CORUM 1 CTD 1 ChEBI 11 ChiTaRS 1 ComplexPortal 3 DNASU 1 DisGeNET 1 EC 2 EMBL 7 Ensembl 3 ExpressionAtlas 1 GO 15 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 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 RNAct 1 Reactome 1 RefSeq 5 Rhea 8 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 SwissPalm 1 TreeFam 1 UCSC 1 UniPathway 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 15616553

Title: The sequence and analysis of duplication-rich human chromosome 16.

PubMed ID: 15616553

DOI: 10.1038/nature03187

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: 9083017

Title: Molecular cloning and characterization of a cDNA encoding the third putative mammalian hyaluronan synthase.

PubMed ID: 9083017

DOI: 10.1074/jbc.272.14.8957

PubMed ID: 23303191

Title: Hyaluronan synthase 1 (HAS1) requires higher cellular UDP-GlcNAc concentration than HAS2 and HAS3.

PubMed ID: 23303191

DOI: 10.1074/jbc.m112.443879

PubMed ID: 25795779

Title: Fluorescence resonance energy transfer (FRET) and proximity ligation assays reveal functionally relevant homo- and heteromeric complexes among hyaluronan synthases HAS1, HAS2, and HAS3.

PubMed ID: 25795779

DOI: 10.1074/jbc.m115.640581

PubMed ID: 26883802

Title: UDP-sugar substrates of HAS3 regulate its O-GlcNAcylation, intracellular traffic, extracellular shedding and correlate with melanoma progression.

PubMed ID: 26883802

DOI: 10.1007/s00018-016-2158-5

PubMed ID: 30394292

Title: Effects of mutations in the post-translational modification sites on the trafficking of hyaluronan synthase 2 (HAS2).

PubMed ID: 30394292

DOI: 10.1016/j.matbio.2018.10.004

Sequence Information:

  • Length: 553
  • Mass: 62998
  • Checksum: 82F3B0C932EE9EA3
  • Sequence:
    • MPVQLTTALR VVGTSLFALA VLGGILAAYV TGYQFIHTEK HYLSFGLYGA ILGLHLLIQS 
LFAFLEHRRM RRAGQALKLP SPRRGSVALC IAAYQEDPDY LRKCLRSAQR ISFPDLKVVM 
VVDGNRQEDA YMLDIFHEVL GGTEQAGFFV WRSNFHEAGE GETEASLQEG MDRVRDVVRA 
STFSCIMQKW GGKREVMYTA FKALGDSVDY IQVCDSDTVL DPACTIEMLR VLEEDPQVGG 
VGGDVQILNK YDSWISFLSS VRYWMAFNVE RACQSYFGCV QCISGPLGMY RNSLLQQFLE 
DWYHQKFLGS KCSFGDDRHL TNRVLSLGYR TKYTARSKCL TETPTKYLRW LNQQTRWSKS 
YFREWLYNSL WFHKHHLWMT YESVVTGFFP FFLIATVIQL FYRGRIWNIL LFLLTVQLVG 
IIKATYACFL RGNAEMIFMS LYSLLYMSSL LPAKIFAIAT INKSGWGTSG RKTIVVNFIG 
LIPVSIWVAV LLGGLAYTAY CQDLFSETEL AFLVSGAILY GCYWVALLML YLAIIARRCG 
KKPEQYSLAF AEV

Genular Protein ID: 3686707703

Symbol: Q96RV2_HUMAN

Name: N/A

UniProtKB Accession Codes:

Q96RV2

Database IDs:

ARBA 2 AlphaFoldDB 1 BRENDA 1 BioGRID-ORCS 1 CAZy 1 CDD 1 CTD 1 ChiTaRS 1 DNASU 1 DisGeNET 1 EMBL 2 GO 5 InterPro 1 NCBI Taxonomy 1 OrthoDB 1 PANTHER 2 PeptideAtlas 1 Pfam 1 PharmGKB 1 RefSeq 1 SAM 1 SUPFAM 1

Citations:

PubMed ID: 11431361

Title: Hyaluronan synthase 3 overexpression promotes the growth of TSU prostate cancer cells.

PubMed ID: 11431361

Sequence Information:

  • Length: 553
  • Mass: 62894
  • Checksum: 75D8E2A3F6BD2469
  • Sequence:
    • MPVQLTTALR VVGTSLFALA VLGGILAAYV TGYQFIHTEK HYLSFGLYGA ILGLHLLIQS 
LFAFLEHRRM QRAGQALKLP SPRRGSVALC IAAYQEDPDY LRKCLRSAQR ISFPDLKVVM 
VVDGNRQEDA YMLDIFHEVL GGTEQAGFFV WRSNFHEAGE GETEASLQEG MDRVRDVVRA 
STFSCIMQKW GGKREVMYTA FKALGDSVDY IQVCDSDTVL DPACTIEMLR VLEEDPQVGG 
VGGDVQILNK YDSWISFLSS VRYWMAFNVE RACQSYFGCV QCISGPLGMY RNSLLQQFLE 
DWYHQKFLGS KCSFGDDRHL TNRVLSLGYR TKYTARSKCL TETPTKYLRW LNQQTRWSKS 
YFREWLYNSL WFHKHHLWMT YESVVTGFFP FFLIATVIQL FYRGRIWNIL LFLLTVQLVG 
IIKATYACFL RGNAEMIFMS LYSLLYMSSL LPAKIFAIAT INKSGWGTSG RKTIVVNFIG 
LIPVSIWVAV LLGGLAYTAY CQDLFSETEL AFLVSGAILY GCYWVALLML YLAIIARRCG 
KKPEQSSLAF AEV