Details for: DENND2D

Gene ID: 79961

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: DENND2D

Ensembl ID: ENSG00000162777

Description: DENN domain containing 2D

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • T follicular helper cell CL0002038
    CSI 13.05
    rCSI 9.76%
    PRS 79.8
  • double negative thymocyte CL0002489
    CSI 12.92
    rCSI 8.98%
    PRS 75.94
  • CD16-positive, CD56-dim natural killer cell, human CL0000939
    CSI 12.48
    rCSI 8.32%
    PRS 83.26
  • CD4-positive helper T cell CL0000492
    CSI 11.45
    rCSI 8.66%
    PRS 78.51
  • helper T cell CL0000912
    CSI 10.84
    rCSI 15.33%
    PRS 68.85
  • epithelial cell of lower respiratory tract CL0002632
    CSI 10.06
    rCSI 7.8%
    PRS 67.22
  • multi-ciliated epithelial cell CL0005012
    CSI 7.93
    rCSI 7.91%
    PRS 58.11
  • CD16-negative, CD56-bright natural killer cell, human CL0000938
    CSI 6.85
    rCSI 5.14%
    PRS 88.95
  • immature B cell CL0000816
    CSI 6.81
    rCSI 5.06%
    PRS 78.01
  • CD4-positive, alpha-beta cytotoxic T cell CL0000934
    CSI 6.53
    rCSI 8.97%
    PRS 83.29
  • central memory CD8-positive, alpha-beta T cell CL0000907
    CSI 4.75
    rCSI 3.2%
    PRS 77.95
  • naive T cell CL0000898
    CSI 4.35
    rCSI 3.03%
    PRS 79.94
  • CD4-positive, alpha-beta thymocyte CL0000810
    CSI 4.31
    rCSI 3.45%
    PRS 83.85
  • Kupffer cell CL0000091
    CSI 3.82
    rCSI 8.74%
    PRS 64.75
  • naive thymus-derived CD8-positive, alpha-beta T cell CL0000900
    CSI 3.65
    rCSI 2.56%
    PRS 82.44
  • effector CD8-positive, alpha-beta T cell CL0001050
    CSI 3.64
    rCSI 2.76%
    PRS 77.79
  • activated CD4-positive, alpha-beta T cell CL0000896
    CSI 3.5
    rCSI 3.24%
    PRS 83.37
  • naive thymus-derived CD4-positive, alpha-beta T cell CL0000895
    CSI 3.35
    rCSI 4.21%
    PRS 88.48
  • alpha-beta T cell CL0000789
    CSI 3.16
    rCSI 3.71%
    PRS 80.71
  • colon epithelial cell CL0011108
    CSI 3.16
    rCSI 3.31%
    PRS 61.12
  • group 3 innate lymphoid cell CL0001071
    CSI 3.01
    rCSI 2.26%
    PRS 70.37
  • activated type II NK T cell CL0000931
    CSI 2.91
    rCSI 3.28%
    PRS 80.84
  • CD4-positive, alpha-beta memory T cell CL0000897
    CSI 2.84
    rCSI 2.04%
    PRS 78.84
  • central memory CD4-positive, alpha-beta T cell CL0000904
    CSI 2.78
    rCSI 1.64%
    PRS 81.89
  • activated CD8-positive, alpha-beta T cell CL0000906
    CSI 2.74
    rCSI 2.69%
    PRS 84.62
  • mature T cell CL0002419
    CSI 2.74
    rCSI 2.13%
    PRS 82.06
  • alveolar macrophage CL0000583
    CSI 2.7
    rCSI 4.44%
    PRS 70.02
  • CD4-positive, CD25-positive, alpha-beta regulatory T cell CL0000792
    CSI 2.68
    rCSI 2.63%
    PRS 80.4
  • T-helper 17 cell CL0000899
    CSI 2.62
    rCSI 2.08%
    PRS 85.15
  • CD8-positive, alpha-beta memory T cell, CD45RO-positive CL0001203
    CSI 2.6
    rCSI 3.14%
    PRS 50.55
  • CD8-positive, alpha-beta thymocyte CL0000811
    CSI 2.56
    rCSI 4%
    PRS 86.84
  • hematopoietic stem cell CL0000037
    CSI 2.44
    rCSI 1.62%
    PRS 67.83
  • intestine goblet cell CL0019031
    CSI 2.4
    rCSI 2.13%
    PRS 62.6
  • renal alpha-intercalated cell CL0005011
    CSI 2.39
    rCSI 3.2%
    PRS 73.65
  • duct epithelial cell CL0000068
    CSI 2.38
    rCSI 3.48%
    PRS 69.78
  • kidney connecting tubule epithelial cell CL1000768
    CSI 2.26
    rCSI 5.73%
    PRS 54.17
  • double negative T regulatory cell CL0011024
    CSI 2.26
    rCSI 42.98%
    PRS 90.79
  • goblet cell CL0000160
    CSI 2.2
    rCSI 2.08%
    PRS 64.07
  • hepatocyte CL0000182
    CSI 2.18
    rCSI 3.9%
    PRS 63.94
  • common myeloid progenitor CL0000049
    CSI 2.12
    rCSI 1.72%
    PRS 66.26
  • ionocyte CL0005006
    CSI 2.08
    rCSI 2.23%
    PRS 64.55
  • ciliated epithelial cell CL0000067
    CSI 2
    rCSI 1.76%
    PRS 52.65
  • effector memory CD8-positive, alpha-beta T cell CL0000913
    CSI 1.99
    rCSI 1.81%
    PRS 79.02
  • elicited macrophage CL0000861
    CSI 1.92
    rCSI 1.76%
    PRS 73.7
  • CD8-positive, alpha-beta cytotoxic T cell CL0000794
    CSI 1.88
    rCSI 2.25%
    PRS 83.56
  • erythrocyte CL0000232
    CSI 1.82
    rCSI 4.14%
    PRS 68.2
  • Hofbauer cell CL3000001
    CSI 1.76
    rCSI 3.32%
    PRS 75.19
  • CD8-positive, CD28-negative, alpha-beta regulatory T cell CL0000920
    CSI 1.67
    rCSI 3.34%
    PRS 81.33
  • natural T-regulatory cell CL0000903
    CSI 1.56
    rCSI 2.96%
    PRS 90.99
  • transit amplifying cell CL0009010
    CSI 1.44
    rCSI 2.21%
    PRS 77.42
  • mature B cell CL0000785
    CSI 1.43
    rCSI 1.24%
    PRS 75.45
  • basal cell of epidermis CL0002187
    CSI 1.4
    rCSI 2.48%
    PRS 37.97
  • mononuclear phagocyte CL0000113
    CSI 1.37
    rCSI 3.02%
    PRS 68.64
  • effector memory CD4-positive, alpha-beta T cell CL0000905
    CSI 1.37
    rCSI 1.87%
    PRS 87.52
  • effector CD4-positive, alpha-beta T cell CL0001044
    CSI 1.33
    rCSI 3.82%
    PRS 84
  • memory T cell CL0000813
    CSI 1.33
    rCSI 2.56%
    PRS 88.77
  • innate lymphoid cell CL0001065
    CSI 1.33
    rCSI 2.75%
    PRS 65.2
  • small intestine goblet cell CL1000495
    CSI 1.24
    rCSI 2.71%
    PRS 72.47
  • activated CD8-positive, alpha-beta T cell, human CL0001049
    CSI 1.22
    rCSI 2.08%
    PRS 81.74
  • mature alpha-beta T cell CL0000791
    CSI 1.06
    rCSI 3.84%
    PRS 83.6
  • germinal center B cell CL0000844
    CSI 1.05
    rCSI 3.13%
    PRS 80.58
  • lung ciliated cell CL1000271
    CSI 0.88
    rCSI 1.02%
    PRS 55.12
  • intraepithelial lymphocyte CL0002496
    CSI 0.86
    rCSI 2.34%
    PRS 90.61
  • intermediate monocyte CL0002393
    CSI 0.8
    rCSI 1.21%
    PRS 69.21
  • hepatic pit cell CL2000054
    CSI 0.75
    rCSI 10.3%
    PRS 88.43
  • CD8-alpha-alpha-positive, alpha-beta intraepithelial T cell CL0000915
    CSI 0.71
    rCSI 3.23%
    PRS 89.42
  • megakaryocyte CL0000556
    CSI 0.59
    rCSI 2.57%
    PRS 76.25
  • effector memory CD8-positive, alpha-beta T cell, terminally differentiated CL0001062
    CSI 0.49
    rCSI 2.46%
    PRS 77.25
  • cytotoxic T cell CL0000910
    CSI 0.23
    rCSI 1.31%
    PRS 73.41

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)

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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 [DENND2D](/details-gene/79961) is a protein-coding gene located on chromosome 1 that encodes the DENN domain-containing protein 2D. This protein functions as a [guanyl-nucleotide exchange factor (GEF)](https://www.ebi.ac.uk/QuickGO/term/GO:0005085), a class of enzymes that activate small GTPases, particularly Rab proteins ([Link](https://doi.org/10.1083/jcb.201008051)). Its involvement in [Rab regulation of trafficking](https://reactome.org/content/detail/R-HSA-9007101) and [vesicle-mediated transport](https://reactome.org/content/detail/R-HSA-5653656) positions it as a key regulator of intracellular membrane dynamics. **Overall**, expression data reveals that [DENND2D](/details-gene/79961) is a significant gene in the immune system, with particularly high significance in lymphocyte populations such as [T follicular helper cell](/details-cell/CL0002038)s and developing [double negative thymocyte](/details-cell/CL0002489)s, suggesting a crucial role in T cell maturation and function. Research also points towards a potential tumor-suppressive role in non-small cell lung cancer ([Link](https://doi.org/10.1016/j.lungcan.2012.10.012)). ## Cellular Roles and Expression Landscape The expression profile of [DENND2D](/details-gene/79961) highlights its prominent role within the hematopoietic system, particularly in adaptive and innate lymphocytes. **Overall**, the gene shows the highest significance in [T follicular helper cell](/details-cell/CL0002038) (CSI: 13.05) and [double negative thymocyte](/details-cell/CL0002489) (CSI: 12.92), indicating a potential function in both mature, specialized T cell subsets and early T cell development in the thymus. The gene's importance extends to other key immune cells, including [CD16-positive, CD56-dim natural killer cell, human](/details-cell/CL0000939) (CSI: 12.48), multiple helper and cytotoxic T cell subsets, and [immature B cell](/details-cell/CL0000816)s. This broad but lymphocyte-focused expression pattern suggests [DENND2D](/details-gene/79961) may regulate fundamental trafficking processes common to these cells, such as cytokine secretion, receptor recycling, or immune synapse formation. Additionally, notable expression is observed in non-immune cells like [epithelial cell of lower respiratory tract](/details-cell/CL0002632) (CSI: 10.06) and [multi-ciliated epithelial cell](/details-cell/CL0005012), consistent with its documented role in lung tissue ([Link](https://doi.org/10.1016/j.lungcan.2012.10.012)). ## Pathways and Molecular Function Functionally, [DENND2D](/details-gene/79961) is annotated as a [guanyl-nucleotide exchange factor (GEF)](https://www.ebi.ac.uk/QuickGO/term/GO:0005085) that catalyzes the exchange of GDP for GTP on Rab family GTPases ([Link](https://doi.org/10.1083/jcb.201008051)). This activation step is a critical control point in [vesicle-mediated transport](https://reactome.org/content/detail/R-HSA-5653656). Its participation in Reactome pathways such as [Rab gefs exchange gtp for gdp on rabs](https://reactome.org/content/detail/R-HSA-8876198) and [membrane trafficking](https://reactome.org/content/detail/R-HSA-199991) confirms its central role in regulating the movement of vesicles within the cell. This molecular function is consistent with its high expression in secretory and highly dynamic immune cells, where precise control over endosomal and exosomal pathways is essential for proper function. The protein is localized to both the [cytosol](https://www.ebi.ac.uk/QuickGO/term/GO:0005829) and [nucleoplasm](https://www.ebi.ac.uk/QuickGO/term/GO:0005654), suggesting it may have diverse subcellular roles. ## Research Directions The functional data and expression patterns of [DENND2D](/details-gene/79961) suggest several avenues for future investigation, particularly concerning its role in immunology and oncology. **Testable Hypotheses:** 1. Given its high significance in [T follicular helper cell](/details-cell/CL0002038)s, [DENND2D](/details-gene/79961) may be essential for the directed trafficking of vesicles containing cytokines (e.g., IL-4, IL-21) and surface receptors (e.g., CD40L) to the immune synapse, a process required for providing help to B cells in the germinal center. 2. The high significance in [double negative thymocyte](/details-cell/CL0002489)s suggests that [DENND2D](/details-gene/79961) regulates the endosomal recycling or degradation of components of the pre-TCR complex, a critical step for proper signaling during beta-selection and progression to the double-positive stage of T cell development. 3. Based on evidence that it suppresses non-small cell lung cancer ([Link](https://doi.org/10.1016/j.lungcan.2012.10.012)), [DENND2D](/details-gene/79961) may function by promoting the endocytic trafficking and subsequent lysosomal degradation of oncogenic receptor tyrosine kinases (e.g., EGFR), thereby attenuating pro-proliferative signaling pathways. **Proposed Experiment:** To test the hypothesis regarding its role in T follicular helper (Tfh) cells (Hypothesis 1), a conditional knockout mouse model using the *Cd4-Cre* system to delete [DENND2D](/details-gene/79961) specifically in T cells could be employed. Following immunization with a T-dependent antigen (e.g., sheep red blood cells or NP-CGG), germinal center formation and Tfh cell function can be assessed. Flow cytometry could be used to quantify Tfh cell numbers and measure surface CD40L expression, while intracellular cytokine staining would reveal defects in IL-21 production. Co-culture of knockout Tfh cells with wild-type B cells would directly test their ability to support B cell proliferation and antibody class-switching in vitro. **Therapeutic Potential:** The existing literature identifies [DENND2D](/details-gene/79961) as a tumor suppressor in lung cancer ([Link](https://doi.org/10.1016/j.lungcan.2012.10.012)). This suggests that therapeutic strategies should focus on **activation** or restoration of its function rather than inhibition. Its role as a GEF presents a druggable enzymatic activity. Potential approaches could include the development of small-molecule agonists that enhance its Rab-GEF activity or gene therapy-based methods to re-introduce its expression in cancer cells where it has been silenced. Such a strategy could restore normal trafficking of growth factor receptors, potentially sensitizing tumors to other therapies.

Genular Protein ID: 2096365371

Symbol: DEN2D_HUMAN

Name: DENN domain-containing protein 2D

UniProtKB Accession Codes:

Q9H6A0 Q5T5V6 Q9BSU0

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CTD 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 3 Ensembl 2 ExpressionAtlas 1 GO 3 Gene3D 2 GeneCards 1 GeneTree 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 6 KEGG 1 MANE-Select 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 3 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 RNAct 1 Reactome 1 RefSeq 2 SMART 3 SMR 1 STRING 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 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: 16710414

Title: The DNA sequence and biological annotation of human chromosome 1.

PubMed ID: 16710414

DOI: 10.1038/nature04727

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: 20937701

Title: Family-wide characterization of the DENN domain Rab GDP-GTP exchange factors.

PubMed ID: 20937701

DOI: 10.1083/jcb.201008051

PubMed ID: 23182661

Title: Suppression of non-small cell lung cancer proliferation and tumorigenicity by DENND2D.

PubMed ID: 23182661

DOI: 10.1016/j.lungcan.2012.10.012

PubMed ID: 24275569

Title: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome.

PubMed ID: 24275569

DOI: 10.1016/j.jprot.2013.11.014

Sequence Information:

  • Length: 471
  • Mass: 53672
  • Checksum: E885FA53369C738C
  • Sequence:
    • MEGQVVGRVF RLFQRRLLQL RAGPPQDNSG EALKEPERAQ EHSLPNFAGG QHFFEYLLVV 
SLKKKRSEDD YEPIITYQFP KRENLLRGQQ EEEERLLKAI PLFCFPDGNE WASLTEYPRE 
TFSFVLTNVD GSRKIGYCRR LLPAGPGPRL PKVYCIISCI GCFGLFSKIL DEVEKRHQIS 
MAVIYPFMQG LREAAFPAPG KTVTLKSFIP DSGTEFISLT RPLDSHLEHV DFSSLLHCLS 
FEQILQIFAS AVLERKIIFL AEGLSTLSQC IHAAAALLYP FSWAHTYIPV VPESLLATVC 
CPTPFMVGVQ MRFQQEVMDS PMEEVLLVNL CEGTFLMSVG DEKDILPPKL QDDILDSLGQ 
GINELKTAEQ INEHVSGPFV QFFVKIVGHY ASYIKREANG QGHFQERSFC KALTSKTNRR 
FVKKFVKTQL FSLFIQEAEK SKNPPAGYFQ QKILEYEEQK KQKKPREKTV K