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    TNIK TRAF2 and NCK interacting kinase [ Homo sapiens (human) ]

    Gene ID: 23043, updated on 14-Nov-2024

    Summary

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    Official Symbol
    TNIKprovided by HGNC
    Official Full Name
    TRAF2 and NCK interacting kinaseprovided by HGNC
    Primary source
    HGNC:HGNC:30765
    See related
    Ensembl:ENSG00000154310 MIM:610005; AllianceGenome:HGNC:30765
    Gene type
    protein coding
    RefSeq status
    REVIEWED
    Organism
    Homo sapiens
    Lineage
    Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
    Also known as
    MRT54
    Summary
    Wnt signaling plays important roles in carcinogenesis and embryonic development. The protein encoded by this gene is a serine/threonine kinase that functions as an activator of the Wnt signaling pathway. Mutations in this gene are associated with an autosomal recessive form of cognitive disability. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2017]
    Expression
    Broad expression in brain (RPKM 10.5), small intestine (RPKM 7.1) and 20 other tissues See more
    Orthologs
    mouse all
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    Genomic context

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    See TNIK in Genome Data Viewer
    Location:
    3q26.2-q26.31
    Exon count:
    34
    Annotation release Status Assembly Chr Location
    RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 3 NC_000003.12 (171058414..171460408, complement)
    RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 3 NC_060927.1 (173842724..174244711, complement)
    RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 3 NC_000003.11 (170776203..171178197, complement)

    Chromosome 3 - NC_000003.12Genomic Context describing neighboring genes Neighboring gene RNA, U1 small nuclear 70, pseudogene Neighboring gene solute carrier family 2 member 2 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14889 Neighboring gene OCT4-NANOG hESC enhancer GRCh37_chr3:170779459-170780037 Neighboring gene MPRA-validated peak4922 silencer Neighboring gene uncharacterized LOC105374216 Neighboring gene OCT4-NANOG hESC enhancer GRCh37_chr3:170834472-170835140 Neighboring gene microRNA 569 Neighboring gene Sharpr-MPRA regulatory region 1564 Neighboring gene Sharpr-MPRA regulatory region 12227 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14890 Neighboring gene NANOG hESC enhancer GRCh37_chr3:170904542-170905069 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 20808 Neighboring gene OCT4-NANOG hESC enhancer GRCh37_chr3:170924049-170924658 Neighboring gene ReSE screen-validated silencer GRCh37_chr3:170952794-170952983 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 20809 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 20810 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 20811 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 20812 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 20813 Neighboring gene VISTA enhancer hs2120 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14892 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 20814 Neighboring gene OCT4-NANOG hESC enhancer GRCh37_chr3:171101812-171102358 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 20815 Neighboring gene uncharacterized LOC124906303 Neighboring gene uncharacterized LOC102724479 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14893 Neighboring gene H3K27ac hESC enhancer GRCh37_chr3:171178895-171179395 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14894 Neighboring gene CRISPRi-validated cis-regulatory element chr3.4898 Neighboring gene CDK7 strongly-dependent group 2 enhancer GRCh37_chr3:171206252-171207451 Neighboring gene RNA, U6 small nuclear 348, pseudogene Neighboring gene MT-CO1 pseudogene 58

    Genomic regions, transcripts, and products

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    Go to nucleotide: Graphics FASTA GenBank

    Expression

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    • Project title: HPA RNA-seq normal tissues HPA RNA-seq normal tissues
    • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
    • BioProject: PRJEB4337
    • Publication: PMID 24309898
    • Analysis date: Wed Apr 4 07:08:55 2018

    Bibliography

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    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. MiR-5590-3p inhibits the proliferation and invasion of ovarian cancer cells through mediating the Wnt/beta-catenin signaling pathway by targeting TNIK.
      Title: MiR-5590-3p inhibits the proliferation and invasion of ovarian cancer cells through mediating the Wnt/β-catenin signaling pathway by targeting TNIK.
    2. The influence of TNIK gene polymorphisms on risperidone response in a Chinese Han population.
      Title: The influence of TNIK gene polymorphisms on risperidone response in a Chinese Han population.
    3. Methylome-wide association study of first-episode schizophrenia reveals a hypermethylated CpG site in the promoter region of the TNIK susceptibility gene.
      Title: Methylome-wide association study of first-episode schizophrenia reveals a hypermethylated CpG site in the promoter region of the TNIK susceptibility gene.
    4. TNIK influence the effects of antipsychotics on Wnt/beta-catenin signaling pathway.
      Title: TNIK influence the effects of antipsychotics on Wnt/β-catenin signaling pathway.
    5. Effect of TNIK upregulation on JQ1-resistant human colorectal cancer HCT116 cells.
      Title: Effect of TNIK upregulation on JQ1-resistant human colorectal cancer HCT116 cells.
    6. We also show that the TNIK protein isoforms including/excluding exon 15 differently regulate cell spreading in non-neuronal cells and neuritogenesis in primary cortical neurons. Our data suggest a complex regulation between the ubiquitous TDP-43 and the neuron-specific NOVA-1 splicing factors in the brain that may help better understand the pathobiology of both neurodegenerative diseases and schizophrenia.
      Title: TDP-43 and NOVA-1 RNA-binding proteins as competitive splicing regulators of the schizophrenia-associated TNIK gene.
    7. Genome-wide association study on the etiology of adolescent idiopathic scoliosis using samples from more than 5 000 patients and 6 000 normal controls showed two genes: LBX1-AS1 on 10q24.32 and TNIK on 3q26.2 highly related to AIS initiation and progression [review]
      Title: [The current review and prospects of the genetic study and clinical treatment of adolescent idiopathic scoliosis].
    8. TNIK is required for the tumour-initiating function of colorectal cancer stem cells. Its inhibition is a promising therapeutic approach.
      Title: TNIK inhibition abrogates colorectal cancer stemness.
    9. Results indicate that Traf2- and Nck-interacting kinase (TNIK) is involved in the interleukin-6-dependent proliferation of multiple myeloma cells.
      Title: Synergistic inhibition effect of TNIK inhibitor KY-05009 and receptor tyrosine kinase inhibitor dovitinib on IL-6-induced proliferation and Wnt signaling pathway in human multiple myeloma cells.
    10. results provide new evidence that TNIK may be involved in the proliferation of multiple myeloma IM-9 cells and in the anti-cancer activity of dovitinib via inhibition of the endogenous Wnt signaling pathway.
      Title: Traf2- and Nck-interacting kinase (TNIK) is involved in the anti-cancer mechanism of dovitinib in human multiple myeloma IM-9 cells.
    Submit: New GeneRIF Correction See all GeneRIFs (23)

    Phenotypes

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    Find tests for this gene in the NIH Genetic Testing Registry (GTR)

    Review eQTL and phenotype association data in this region using PheGenI

    Associated conditions

    Description Tests
    Intellectual disability, autosomal recessive 54
    MedGen: C4310755 OMIM: 617028 GeneReviews: Not available
    		Compare labs

    EBI GWAS Catalog

    Description
    A genome-wide association study of schizophrenia using brain activation as a quantitative phenotype.
    EBI GWAS Catalog
    Genome-wide association study of coronary heart disease and its risk factors in 8,090 African Americans: the NHLBI CARe Project.
    EBI GWAS Catalog

    Variation

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    See Variation Viewer (GRCh37.p13)

    Pathways from PubChem

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    Interactions

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    Products Interactant Other Gene Complex Source Pubs Description

    General gene information

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    Markers

    Homology

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    enables 3-phosphoinositide-dependent protein kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables AMP-activated protein kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables ATP binding IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables DNA-dependent protein kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables Rho-dependent protein serine/threonine kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables eukaryotic translation initiation factor 2alpha kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables histone H2AS1 kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables histone H2AS121 kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables histone H2AT120 kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables histone H2AXS139 kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables histone H2BS14 kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables histone H2BS36 kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables histone H3S10 kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables histone H3S28 kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables histone H3S57 kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables histone H3T11 kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables histone H3T3 kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables histone H3T45 kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables histone H3T6 kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables histone H4S1 kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables protein binding IPI
    Inferred from Physical Interaction
    more info
    		 PubMed 
    enables protein kinase activity IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables protein serine kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    enables protein serine/threonine kinase activity IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    enables protein serine/threonine kinase activity IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    enables ribosomal protein S6 kinase activity IEA
    Inferred from Electronic Annotation
    more info
    		  
    Process Evidence Code Pubs
    involved_in MAPK cascade IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in Wnt signaling pathway IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in actin cytoskeleton organization IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in chromatin remodeling IEA
    Inferred from Electronic Annotation
    more info
    		  
    involved_in cytoskeleton organization IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in intracellular signal transduction IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in microvillus assembly IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in neuron projection morphogenesis IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in positive regulation of JNK cascade IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in positive regulation of JNK cascade IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in positive regulation of protein phosphorylation IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in protein autophosphorylation IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in protein localization to plasma membrane IMP
    Inferred from Mutant Phenotype
    more info
    		 PubMed 
    involved_in protein phosphorylation IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    involved_in regulation of MAPK cascade IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    involved_in regulation of dendrite morphogenesis IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    Component Evidence Code Pubs
    located_in apical plasma membrane IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    is_active_in cytoplasm IBA
    Inferred from Biological aspect of Ancestor
    more info
    		  
    located_in cytoplasm IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in cytoskeleton IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in cytosol IDA
    Inferred from Direct Assay
    more info
    		  
    located_in extracellular exosome HDA PubMed 
    located_in glutamatergic synapse IEA
    Inferred from Electronic Annotation
    more info
    		  
    located_in nucleoplasm IDA
    Inferred from Direct Assay
    more info
    		  
    located_in nucleus IDA
    Inferred from Direct Assay
    more info
    		 PubMed 
    located_in postsynaptic density, intracellular component IEA
    Inferred from Electronic Annotation
    more info
    		  
    located_in presynapse IEA
    Inferred from Electronic Annotation
    more info
    		  
    located_in recycling endosome IEA
    Inferred from Electronic Annotation
    more info
    		  

    General protein information

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    Preferred Names
    TRAF2 and NCK-interacting protein kinase
    NP_001155032.1
    NP_001155033.1
    NP_001155034.1
    NP_001155035.1
    NP_001155036.1
    NP_001155037.1
    NP_001155038.1
    NP_055843.1

    NCBI Reference Sequences (RefSeq)

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    NEW Try the new Transcript table

    RefSeqs maintained independently of Annotated Genomes

    These reference sequences exist independently of genome builds. Explain

    These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

    Genomic

    1. NG_054934.2 RefSeqGene

      Range
      5003..406994
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. NM_001161560.3 → NP_001155032.1  TRAF2 and NCK-interacting protein kinase isoform 2

      See identical proteins and their annotated locations for NP_001155032.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) lacks an in-frame exon in the middle portion of the coding region compared to variant 1. This results in a shorter protein (isoform 2) compared to isoform 1.
      Source sequence(s)
      AC026315, AC078793, AC092919, AC137517
      Consensus CDS
      CCDS54679.1
      UniProtKB/Swiss-Prot
      Q9UKE5
      Related
      ENSP00000284483.8, ENST00000284483.12
      Conserved Domains (2) summary
      smart00036
      Location:1034 → 1332
      CNH; Domain found in NIK1-like kinases, mouse citron and yeast ROM1, ROM2
      cd06637
      Location:18 → 313
      STKc_TNIK; Catalytic domain of the Serine/Threonine Kinase, Traf2- and Nck-Interacting Kinase

    2. NM_001161561.3 → NP_001155033.1  TRAF2 and NCK-interacting protein kinase isoform 3

      See identical proteins and their annotated locations for NP_001155033.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (3) lacks an in-frame exon in the middle portion of the coding region compared to variant 1. This results in a shorter protein (isoform 3) compared to isoform 1.
      Source sequence(s)
      AC026315, AC078793, AC092919, AC137517
      Consensus CDS
      CCDS54676.1
      UniProtKB/Swiss-Prot
      Q9UKE5
      Related
      ENSP00000349880.5, ENST00000357327.9
      Conserved Domains (2) summary
      smart00036
      Location:1013 → 1311
      CNH; Domain found in NIK1-like kinases, mouse citron and yeast ROM1, ROM2
      cd06637
      Location:18 → 313
      STKc_TNIK; Catalytic domain of the Serine/Threonine Kinase, Traf2- and Nck-Interacting Kinase

    3. NM_001161562.3 → NP_001155034.1  TRAF2 and NCK-interacting protein kinase isoform 4

      See identical proteins and their annotated locations for NP_001155034.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (4) lacks two in-frame exons in the middle portion of the coding region compared to variant 1. This results in a shorter protein (isoform 4) compared to isoform 1.
      Source sequence(s)
      AC026315, AC078793, AC092919, AC137517
      Consensus CDS
      CCDS54675.1
      UniProtKB/Swiss-Prot
      Q9UKE5
      Related
      ENSP00000419990.1, ENST00000470834.5
      Conserved Domains (2) summary
      smart00036
      Location:1005 → 1303
      CNH; Domain found in NIK1-like kinases, mouse citron and yeast ROM1, ROM2
      cd06637
      Location:18 → 313
      STKc_TNIK; Catalytic domain of the Serine/Threonine Kinase, Traf2- and Nck-Interacting Kinase

    4. NM_001161563.3 → NP_001155035.1  TRAF2 and NCK-interacting protein kinase isoform 5

      See identical proteins and their annotated locations for NP_001155035.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (5) lacks an in-frame exon in the middle portion of the coding region compared to variant 1. This results in a shorter protein (isoform 5) compared to isoform 1.
      Source sequence(s)
      AC026315, AC078793, AC092919, AC137517
      Consensus CDS
      CCDS54678.1
      UniProtKB/Swiss-Prot
      Q9UKE5
      Related
      ENSP00000418378.1, ENST00000488470.5
      Conserved Domains (3) summary
      smart00036
      Location:987 → 1285
      CNH; Domain found in NIK1-like kinases, mouse citron and yeast ROM1, ROM2
      smart00220
      Location:25 → 289
      S_TKc; Serine/Threonine protein kinases, catalytic domain
      cd06637
      Location:18 → 313
      STKc_TNIK; Catalytic domain of the Serine/Threonine Kinase, Traf2- and Nck-Interacting Kinase

    5. NM_001161564.3 → NP_001155036.1  TRAF2 and NCK-interacting protein kinase isoform 6

      See identical proteins and their annotated locations for NP_001155036.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (6) lacks two in-frame exons in the middle portion of the coding region compared to variant 1. This results in a shorter protein (isoform 6) compared to isoform 1.
      Source sequence(s)
      AC026315, AC078793, AC092919, AC137517
      Consensus CDS
      CCDS54677.1
      UniProtKB/Swiss-Prot
      Q9UKE5
      Related
      ENSP00000418916.1, ENST00000460047.5
      Conserved Domains (3) summary
      smart00036
      Location:979 → 1277
      CNH; Domain found in NIK1-like kinases, mouse citron and yeast ROM1, ROM2
      smart00220
      Location:25 → 289
      S_TKc; Serine/Threonine protein kinases, catalytic domain
      cd06637
      Location:18 → 313
      STKc_TNIK; Catalytic domain of the Serine/Threonine Kinase, Traf2- and Nck-Interacting Kinase

    6. NM_001161565.3 → NP_001155037.1  TRAF2 and NCK-interacting protein kinase isoform 7

      See identical proteins and their annotated locations for NP_001155037.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (7) lacks two in-frame exons in the middle portion of the coding region compared to variant 1. This results in a shorter protein (isoform 7) compared to isoform 1.
      Source sequence(s)
      AC026315, AC078793, AC092919, AC137517
      Consensus CDS
      CCDS54674.1
      UniProtKB/Swiss-Prot
      Q9UKE5
      Related
      ENSP00000345352.6, ENST00000341852.10
      Conserved Domains (3) summary
      smart00036
      Location:958 → 1256
      CNH; Domain found in NIK1-like kinases, mouse citron and yeast ROM1, ROM2
      smart00220
      Location:25 → 289
      S_TKc; Serine/Threonine protein kinases, catalytic domain
      cd06637
      Location:18 → 313
      STKc_TNIK; Catalytic domain of the Serine/Threonine Kinase, Traf2- and Nck-Interacting Kinase

    7. NM_001161566.3 → NP_001155038.1  TRAF2 and NCK-interacting protein kinase isoform 8

      See identical proteins and their annotated locations for NP_001155038.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (8) lacks three in-frame exons in the middle portion of the coding region compared to variant 1. This results in a shorter protein (isoform 8) compared to isoform 1.
      Source sequence(s)
      AC026315, AC078793, AC092919, AC137517
      Consensus CDS
      CCDS54673.1
      UniProtKB/Swiss-Prot
      Q9UKE5
      Related
      ENSP00000418156.1, ENST00000475336.5
      Conserved Domains (3) summary
      smart00036
      Location:950 → 1248
      CNH; Domain found in NIK1-like kinases, mouse citron and yeast ROM1, ROM2
      smart00220
      Location:25 → 289
      S_TKc; Serine/Threonine protein kinases, catalytic domain
      cd06637
      Location:18 → 313
      STKc_TNIK; Catalytic domain of the Serine/Threonine Kinase, Traf2- and Nck-Interacting Kinase

    8. NM_015028.4 → NP_055843.1  TRAF2 and NCK-interacting protein kinase isoform 1

      See identical proteins and their annotated locations for NP_055843.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) represents the longest transcript and encodes the longest isoform (1).
      Source sequence(s)
      AC026315, AC078793, AC092919, AC137517
      Consensus CDS
      CCDS46956.1
      UniProtKB/Swiss-Prot
      A7E2A3, A8K4U1, D3DNQ6, O60298, Q8WUY7, Q9UKD8, Q9UKD9, Q9UKE0, Q9UKE1, Q9UKE2, Q9UKE3, Q9UKE4, Q9UKE5
      Related
      ENSP00000399511.2, ENST00000436636.7
      Conserved Domains (2) summary
      smart00036
      Location:1042 → 1340
      CNH; Domain found in NIK1-like kinases, mouse citron and yeast ROM1, ROM2
      cd06637
      Location:18 → 313
      STKc_TNIK; Catalytic domain of the Serine/Threonine Kinase, Traf2- and Nck-Interacting Kinase

    RNA

    1. NR_027767.2 RNA Sequence

      Status: REVIEWED

      Source sequence(s)
      AK291056, AW296249, BC018093, BG209385
      Related
      ENST00000465393.1

    RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2024_08

    The following sections contain reference sequences that belong to a specific genome build. Explain

    Reference GRCh38.p14 Primary Assembly

    Genomic

    1. NC_000003.12 Reference GRCh38.p14 Primary Assembly

      Range
      171058414..171460408 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060927.1 Alternate T2T-CHM13v2.0

      Range
      173842724..174244711 complement
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)
    Nucleotide Protein
    Heading Accession and Version
    Protein Accession Links
    GenPept Link UniProtKB Link
    Q9UKE5.1 GenPept UniProtKB/Swiss-Prot:Q9UKE5

    Gene LinkOut

    The following LinkOut resources are supplied by external providers. These providers are responsible for maintaining the links.

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