Details for: TGFBRAP1

Gene ID: 9392

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: TGFBRAP1

Ensembl ID: ENSG00000135966

Description: transforming growth factor beta receptor associated protein 1

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • neural progenitor cell CL0011020
    CSI 4.51
    rCSI 19.85%
    PRS 87.64
  • mucosal invariant T cell CL0000940
    CSI 4.19
    rCSI 3.38%
    PRS 97.96
  • Kupffer cell CL0000091
    CSI 4.15
    rCSI 9.48%
    PRS 96.44
  • melanocyte CL0000148
    CSI 3.73
    rCSI 2.76%
    PRS 93.66
  • hematopoietic stem cell CL0000037
    CSI 3.03
    rCSI 2.02%
    PRS 96.51
  • pancreatic A cell CL0000171
    CSI 3
    rCSI 3.14%
    PRS 96.3
  • megakaryocyte-erythroid progenitor cell CL0000050
    CSI 2.8
    rCSI 2.53%
    PRS 95.11
  • choroid plexus epithelial cell CL0000706
    CSI 2.8
    rCSI 4.59%
    PRS 91.64
  • hepatic stellate cell CL0000632
    CSI 2.8
    rCSI 10.47%
    PRS 93.88
  • cerebral cortex endothelial cell CL1001602
    CSI 2.75
    rCSI 4.76%
    PRS 92.98
  • vascular leptomeningeal cell CL4023051
    CSI 2.6
    rCSI 4.56%
    PRS 94.04
  • common myeloid progenitor CL0000049
    CSI 2.42
    rCSI 1.96%
    PRS 96.51
  • pvalb GABAergic cortical interneuron CL4023018
    CSI 2.32
    rCSI 2.89%
    PRS 86.51
  • caudal ganglionic eminence derived cortical interneuron CL4023064
    CSI 2.27
    rCSI 4%
    PRS 87.88
  • astrocyte of the cerebral cortex CL0002605
    CSI 2.13
    rCSI 4.77%
    PRS 88.62
  • VIP GABAergic cortical interneuron CL4023016
    CSI 1.87
    rCSI 2.23%
    PRS 88.38
  • lamp5 GABAergic cortical interneuron CL4023011
    CSI 1.81
    rCSI 3.03%
    PRS 88.36
  • sncg GABAergic cortical interneuron CL4023015
    CSI 1.69
    rCSI 2.71%
    PRS 89.13
  • hematopoietic multipotent progenitor cell CL0000837
    CSI 1.05
    rCSI 2.52%
    PRS 98.51
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 1.01
    rCSI 2.47%
    PRS 86.57
  • lymphoid lineage restricted progenitor cell CL0000838
    CSI 0.95
    rCSI 3.7%
    PRS 99.34
  • L6b glutamatergic cortical neuron CL4023038
    CSI 0.79
    rCSI 2.47%
    PRS 89.11
  • chandelier pvalb GABAergic cortical interneuron CL4023036
    CSI 0.74
    rCSI 2.31%
    PRS 90.41
  • corticothalamic-projecting glutamatergic cortical neuron CL4023013
    CSI 0.72
    rCSI 4.25%
    PRS 88.66
  • near-projecting glutamatergic cortical neuron CL4023012
    CSI 0.66
    rCSI 2.5%
    PRS 88.33
  • L5 extratelencephalic projecting glutamatergic cortical neuron CL4023041
    CSI 0.66
    rCSI 2.37%
    PRS 86.76

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.

Comma-separated if multiple.
Comma-separated if multiple.
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)

Loading network (please wait)...

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 [TGFBRAP1](/details-gene/9392), or Transforming Growth Factor Beta Receptor Associated Protein 1, encodes an intracellular protein that functions as a key signaling intermediate and trafficking regulator. Its primary role involves participation in the [Transforming growth factor beta receptor signaling pathway](/details-go/GO:0007179), where it acts as a chaperone for SMAD4, facilitating the transduction of TGF-beta signals from the cell surface receptor to the nucleus ([Link](https://doi.org/10.1074/jbc.m006473200)). Additionally, [TGFBRAP1](/details-gene/9392) is an integral component of the CORVET complex, which is essential for endosomal trafficking, fusion, and [Autophagy](/details-go/GO:0006914) ([Link](https://doi.org/10.1111/tra.12232)). Reflecting these fundamental cellular roles, its expression is significant across a diverse array of cell types, including high significance in progenitor populations like [neural progenitor cells](/details-cell/CL0011020) and [hematopoietic stem cells](/details-cell/CL0000037), as well as in specialized immune cells such as [mucosal invariant T cells](/details-cell/CL0000940) and [Kupffer cells](/details-cell/CL0000091). ## Cellular Roles and Expression Landscape The **Overall** expression profile of [TGFBRAP1](/details-gene/9392) suggests its widespread importance in cellular homeostasis, signaling, and development across multiple tissues. A prominent feature is its high significance in various progenitor and stem cell populations, including [neural progenitor cells](/details-cell/CL0011020) (CSI: 4.51), [hematopoietic stem cells](/details-cell/CL0000037) (CSI: 3.03), [megakaryocyte-erythroid progenitor cells](/details-cell/CL0000050) (CSI: 2.80), and [common myeloid progenitors](/details-cell/CL0000049) (CSI: 2.42). This pattern is consistent with its established role in the TGF-beta pathway, a critical regulator of cell fate, differentiation, and pluripotency. Beyond progenitor cells, [TGFBRAP1](/details-gene/9392) demonstrates significant expression in the central nervous system and the immune system. It is a notable marker in various neural cell types, including [choroid plexus epithelial cells](/details-cell/CL0000706), [cerebral cortex endothelial cells](/details-cell/CL1001602), multiple classes of cortical interneurons, and [astrocytes of the cerebral cortex](/details-cell/CL0002605). In the immune compartment, its high significance in [mucosal invariant T cells](/details-cell/CL0000940) and the liver-resident macrophages known as [Kupffer cells](/details-cell/CL0000091) suggests a potential role in innate-like T cell function and tissue-specific macrophage activity. The gene is also highly expressed in other specialized cells like [melanocytes](/details-cell/CL0000148), [pancreatic A cells](/details-cell/CL0000171), and [hepatic stellate cells](/details-cell/CL0000632), underscoring its broad functional relevance. ## Pathways and Molecular Function The molecular functions of [TGFBRAP1](/details-gene/9392) are centered on two interconnected cellular processes: signal transduction and intracellular vesicle trafficking. Its best-characterized role is as a mediator in the [Transforming growth factor beta receptor signaling pathway](/details-go/GO:0007179). Functional annotations confirm its ability for [Transforming growth factor beta receptor binding](/details-go/GO:0005160) and, critically, [Smad binding](/details-go/GO:0046332). Research has shown that it acts as a chaperone for the common-mediator Smad, SMAD4, ensuring its proper function in the signaling cascade that regulates [dna-templated transcription](/details-go/GO:0006355) ([Link](https://doi.org/10.1074/jbc.m006473200)). This function directly links environmental cues received by the TGF-beta receptor to changes in gene expression, a process vital for development and tissue homeostasis. Concurrently, [TGFBRAP1](/details-gene/9392) is a key player in endo-lysosomal trafficking. It is a core component of the [CORVET complex](/details-go/GO:0033263), a multisubunit tethering complex that mediates the fusion of early endosomes ([Link](https://doi.org/10.1111/tra.12232)). This role is reflected in its association with biological processes such as [Endosomal vesicle fusion](/details-go/GO:0034058), [Endosome to lysosome transport](/details-go/GO:0008333), and [Autophagy](/details-go/GO:0006914). This trafficking function is essential for protein degradation, nutrient recycling, and the correct localization of signaling receptors, potentially including the TGF-beta receptor itself. ## Research Directions The dual functionality of [TGFBRAP1](/details-gene/9392) in both a canonical signaling pathway and a core trafficking machinery presents several avenues for future investigation. Its widespread expression pattern suggests that its specific impact may be highly context-dependent. **Proposed Hypotheses:** 1. Given its high significance in [neural progenitor cells](/details-cell/CL0011020) and [hematopoietic stem cells](/details-cell/CL0000037), and its role as a SMAD4 chaperone, it is hypothesized that **[TGFBRAP1](/details-gene/9392) expression levels fine-tune the sensitivity of progenitor cells to TGF-beta family ligands, thereby acting as a rheostat that governs the critical decision between self-renewal and lineage commitment.** 2. Based on its function in the CORVET complex and high expression in [Kupffer cells](/details-cell/CL0000091), a cell type with high phagocytic and endocytic activity, it is hypothesized that **[TGFBRAP1](/details-gene/9392) is essential for the maturation of phagosomes and endosomes in tissue-resident macrophages, and its disruption impairs their ability to process and present antigens or clear cellular debris.** **Experimental Approach:** To test the first hypothesis regarding the role of [TGFBRAP1](/details-gene/9392) in progenitor cell fate, a combination of genetic and cell biology approaches could be employed. One could utilize a human induced pluripotent stem cell (iPSC) model and generate a [TGFBRAP1](/details-gene/9392) knockout line using CRISPR-Cas9. Wild-type and knockout iPSCs would then be directed to differentiate towards a specific lineage, such as neuroectoderm. The differentiation process would be monitored over time using single-cell RNA sequencing (scRNA-seq) to map cellular trajectories and identify points of divergence. Furthermore, a quantitative phosphoproteomics analysis of key TGF-beta pathway components, such as SMAD2/3, following stimulation with TGF-beta would reveal if the loss of [TGFBRAP1](/details-gene/9392) alters the dynamics or magnitude of the downstream signaling response. **Therapeutic Potential:** As an intracellular adaptor protein integral to the TGF-beta pathway, which is frequently dysregulated in cancer and fibrotic diseases, [TGFBRAP1](/details-gene/9392) presents a potential therapeutic target. The strategy would focus on **inhibition** to dampen pro-tumorigenic or pro-fibrotic TGF-beta signaling. However, its nature as a scaffolding protein without a defined enzymatic active site makes it a challenging target for traditional small molecule inhibitors. A more viable strategy could involve developing molecules that disrupt the protein-protein interaction between [TGFBRAP1](/details-gene/9392) and SMAD4 or the TGF-beta receptor. Given the gene's broad expression and fundamental role in endosomal trafficking, systemic inhibition carries a high risk of toxicity. Therefore, any therapeutic approach would likely require targeted delivery systems to confine the inhibitory effect to the specific diseased tissue.

Genular Protein ID: 892186986

Symbol: TGFA1_HUMAN

Name: Transforming growth factor-beta receptor-associated protein 1

UniProtKB Accession Codes:

Q8WUH2 A8K5R7 D3DVJ8 O60466

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CORUM 1 CTD 1 ChiTaRS 1 ComplexPortal 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 6 Ensembl 2 GO 15 GeneCards 1 GeneTree 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 5 KEGG 1 MANE-Select 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PIR 1 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 4 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 Pumba 1 RNAct 1 RefSeq 2 SIGNOR 1 SMR 1 STRING 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 9545258

Title: A novel protein distinguishes between quiescent and activated forms of the type I transforming growth factor beta receptor.

PubMed ID: 9545258

DOI: 10.1074/jbc.273.16.9365

PubMed ID: 14702039

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

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 15815621

Title: Generation and annotation of the DNA sequences of human chromosomes 2 and 4.

PubMed ID: 15815621

DOI: 10.1038/nature03466

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: 10051563

Title: Interaction of 5-lipoxygenase with cellular proteins.

PubMed ID: 10051563

DOI: 10.1073/pnas.96.5.1881

PubMed ID: 11278302

Title: Transforming growth factor-beta receptor-associated protein 1 is a Smad4 chaperone.

PubMed ID: 11278302

DOI: 10.1074/jbc.m006473200

PubMed ID: 20068231

Title: Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis.

PubMed ID: 20068231

DOI: 10.1126/scisignal.2000475

PubMed ID: 25266290

Title: Mammalian CORVET is required for fusion and conversion of distinct early endosome subpopulations.

PubMed ID: 25266290

DOI: 10.1111/tra.12232

Sequence Information:

  • Length: 860
  • Mass: 97158
  • Checksum: ABDD23BEDC5F4A55
  • Sequence:
    • MMSIKAFTLV SAVERELLMG DKERVNIECV ECCGRDLYVG TNDCFVYHFL LEERPVPAGP 
ATFTATKQLQ RHLGFKKPVN ELRAASALNR LLVLCDNSIS LVNMLNLEPV PSGARIKGAA 
TFALNENPVS GDPFCVEVCI ISVKRRTIQM FLVYEDRVQI VKEVSTAEQP LAVAVDGHFL 
CLALTTQYII HNYSTGVSQD LFPYCSEERP PIVKRIGRQE FLLAGPGGLG MFATVAGISQ 
RAPVHWSENV IGAAVSFPYV IALDDEFITV HSMLDQQQKQ TLPFKEGHIL QDFEGRVIVA 
TSKGVYILVP LPLEKQIQDL LASRRVEEAL VLAKGARRNI PKEKFQVMYR RILQQAGFIQ 
FAQLQFLEAK ELFRSGQLDV RELISLYPFL LPTSSSFTRS HPPLHEYADL NQLTQGDQEK 
MAKCKRFLMS YLNEVRSTEV ANGYKEDIDT ALLKLYAEAD HDSLLDLLVT ENFCLLTDSA 
AWLEKHKKYF ALGLLYHYNN QDAAAVQLWV NIVNGDVQDS TRSDLYEYIV DFLTYCLDEE 
LVWAYADWVL QKSEEVGVQV FTKRPLDEQQ KNSFNPDDII NCLKKYPKAL VKYLEHLVID 
KRLQKEEYHT HLAVLYLEEV LLQRASASGK GAEATETQAK LRRLLQKSDL YRVHFLLERL 
QGAGLPMESA ILHGKLGEHE KALHILVHEL QDFAAAEDYC LWCSEGRDPP HRQQLFHTLL 
AIYLHAGPTA HELAVAAVDL LNRHATEFDA AQVLQMLPDT WSVQLLCPFL MGAMRDSIHA 
RRTMQVALGL ARSENLIYTY DKMKLKGSSI QLSDKKLCQI CQNPFCEPVF VRYPNGGLVH 
THCAASRHTN PSSSSPGTRT