Details for: SH3RF2

Gene ID: 153769

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: SH3RF2

Ensembl ID: ENSG00000156463

Description: SH3 domain containing ring finger 2

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • ventricular cardiac muscle cell CL2000046
    CSI 7.57
    rCSI 25.93%
    PRS 90.32
  • luminal epithelial cell of mammary gland CL0002326
    CSI 4.81
    rCSI 8.74%
    PRS 91.95
  • duct epithelial cell CL0000068
    CSI 3.88
    rCSI 5.67%
    PRS 88.5
  • conjunctival epithelial cell CL1000432
    CSI 3.69
    rCSI 5.64%
    PRS 84.01
  • colon epithelial cell CL0011108
    CSI 3.63
    rCSI 3.8%
    PRS 81.59
  • regular atrial cardiac myocyte CL0002129
    CSI 3.58
    rCSI 11.51%
    PRS 80.91
  • respiratory hillock cell CL4030023
    CSI 3.38
    rCSI 6.02%
    PRS 90.64
  • secretory cell CL0000151
    CSI 3.14
    rCSI 3.28%
    PRS 83.39
  • corneal epithelial cell CL0000575
    CSI 2.92
    rCSI 8.36%
    PRS 88.56
  • pancreatic acinar cell CL0002064
    CSI 2.72
    rCSI 3.61%
    PRS 88.73
  • endocardial cell CL0002350
    CSI 2.67
    rCSI 12.8%
    PRS 80.18
  • parietal epithelial cell CL1000452
    CSI 2.66
    rCSI 7.1%
    PRS 76.79
  • keratinocyte CL0000312
    CSI 2.63
    rCSI 2.2%
    PRS 86.05
  • lung secretory cell CL1000272
    CSI 2.5
    rCSI 6.19%
    PRS 84.34
  • intestinal epithelial cell CL0002563
    CSI 2.48
    rCSI 2.6%
    PRS 81.7
  • paneth cell of epithelium of small intestine CL1000343
    CSI 2.38
    rCSI 6.67%
    PRS 89.46
  • hepatocyte CL0000182
    CSI 2.28
    rCSI 4.09%
    PRS 83.33
  • cerebral cortex endothelial cell CL1001602
    CSI 2.27
    rCSI 3.93%
    PRS 76.47
  • respiratory suprabasal cell CL4033048
    CSI 2.21
    rCSI 2.83%
    PRS 86.79
  • adipocyte CL0000136
    CSI 2.19
    rCSI 2.81%
    PRS 74.75
  • transit amplifying cell of colon CL0009011
    CSI 2.16
    rCSI 2.54%
    PRS 85.5
  • intrahepatic cholangiocyte CL0002538
    CSI 2.15
    rCSI 5.17%
    PRS 86.59
  • ependymal cell CL0000065
    CSI 2.13
    rCSI 4.32%
    PRS 63.87
  • intestinal crypt stem cell of small intestine CL0009017
    CSI 2.13
    rCSI 5.73%
    PRS 87.77
  • BEST4+ enteroycte CL4030026
    CSI 1.96
    rCSI 2.44%
    PRS 84.73
  • Schwann cell CL0002573
    CSI 1.88
    rCSI 5.34%
    PRS 79.92
  • direct pathway medium spiny neuron CL4023026
    CSI 1.8
    rCSI 43.09%
    PRS 65.39
  • indirect pathway medium spiny neuron CL4023029
    CSI 1.78
    rCSI 42.95%
    PRS 65.86
  • colonocyte CL1000347
    CSI 1.78
    rCSI 2.55%
    PRS 83.87
  • cardiac muscle cell CL0000746
    CSI 1.71
    rCSI 2.46%
    PRS 74.63
  • basal cell CL0000646
    CSI 1.66
    rCSI 2.21%
    PRS 82.08
  • club cell CL0000158
    CSI 1.65
    rCSI 2.42%
    PRS 79.07
  • squamous epithelial cell CL0000076
    CSI 1.54
    rCSI 3.66%
    PRS 83.24
  • basal-myoepithelial cell of mammary gland CL0002324
    CSI 1.53
    rCSI 2.88%
    PRS 92.15
  • small intestine goblet cell CL1000495
    CSI 1.52
    rCSI 3.32%
    PRS 88.35
  • foveolar cell of stomach CL0002179
    CSI 1.28
    rCSI 2.71%
    PRS 88.77
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 1.21
    rCSI 2.95%
    PRS 65.32
  • pulmonary alveolar type 1 cell CL0002062
    CSI 1.02
    rCSI 5.88%
    PRS 80.53
  • L6b glutamatergic cortical neuron CL4023038
    CSI 0.9
    rCSI 2.81%
    PRS 69
  • transit amplifying cell of small intestine CL0009012
    CSI 0.89
    rCSI 3.9%
    PRS 90.22
  • enterocyte of epithelium of large intestine CL0002071
    CSI 0.79
    rCSI 4.17%
    PRS 88.11
  • medium spiny neuron CL1001474
    CSI 0.73
    rCSI 6.32%
    PRS 73.08
  • regular ventricular cardiac myocyte CL0002131
    CSI 0.71
    rCSI 4.46%
    PRS 76.51
  • intestinal crypt stem cell of colon CL0009043
    CSI 0.48
    rCSI 3.61%
    PRS 91.61
  • central nervous system neuron CL2000029
    CSI 0.42
    rCSI 3.05%
    PRS 72.63

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 [SH3RF2](/details-gene/153769), or SH3 Domain Containing RING Finger 2, encodes an E3 ubiquitin-protein ligase involved in critical cellular processes, including the regulation of protein ubiquitination, apoptosis, and JNK signaling cascades. Expression data indicate that [SH3RF2](/details-gene/153769) has a particularly significant role in cardiac muscle tissue, showing the highest level of significance in [ventricular cardiac muscle cell](/details-cell/CL2000046). It is also prominently expressed across a diverse range of epithelial tissues, including the mammary gland ([luminal epithelial cell of mammary gland](/details-cell/CL0002326)) and various ductal systems ([duct epithelial cell](/details-cell/CL0000068)), suggesting a fundamental function in the maintenance and physiology of these cell types. ## Cellular Roles and Expression Landscape The expression profile of [SH3RF2](/details-gene/153769) points to specialized functions primarily within cardiac and epithelial tissues. **Overall**, its most significant expression is observed in [ventricular cardiac muscle cell](/details-cell/CL2000046) (CSI: 7.57), a finding consistent with its initial characterization as a heart protein phosphatase 1-binding protein ([Link](https://doi.org/10.1016/j.bbrc.2009.11.123)). Its relevance in the heart is further supported by notable expression in [regular atrial cardiac myocyte](/details-cell/CL0002129) and [endocardial cell](/details-cell/CL0002350). Beyond the heart, [SH3RF2](/details-gene/153769) is a key gene in numerous epithelial lineages. It shows high significance in secretory and barrier-forming cells such as [luminal epithelial cell of mammary gland](/details-cell/CL0002326), [duct epithelial cell](/details-cell/CL0000068), [conjunctival epithelial cell](/details-cell/CL1000432), [colon epithelial cell](/details-cell/CL0011108), and [keratinocyte](/details-cell/CL0000312). This broad expression pattern in epithelial cells suggests a conserved role in tissue homeostasis, cell migration, or survival pathways. The general absence of hematopoietic or neuronal cell types from the top-expressed list implies that its primary functions are likely concentrated outside of the immune and nervous systems. ## Pathways and Molecular Function The primary molecular function of [SH3RF2](/details-gene/153769) is its [ubiquitin protein ligase activity](/details-go/GO:0061630), enabling it to mediate [protein ubiquitination](/details-go/GO:0016567) and [protein autoubiquitination](/details-go/GO:0051865). This E3 ligase activity targets proteins for degradation via the proteasome, as indicated by its role in the [positive regulation of proteasomal ubiquitin-dependent protein catabolic process](/details-go/GO:0032436). One key substrate is the JNK scaffold protein POSH, whose degradation by [SH3RF2](/details-gene/153769) promotes cell survival ([Link](https://doi.org/10.1074/jbc.m111.269431)). This enzymatic function underlies its involvement in several key biological processes. [SH3RF2](/details-gene/153769) is an important regulator of cellular signaling, with documented roles in both the [positive regulation of jnk cascade](/details-go/GO:0046330) and [negative regulation of jnk cascade](/details-go/GO:0046329), suggesting a context-dependent modulatory role. Consistent with its pro-survival functions, it is also involved in the [negative regulation of apoptotic process](/details-go/GO:0043066). Further, its function is modulated by protein-protein interactions, including binding to phosphatases ([phosphatase binding](/details-go/GO:0019902)), particularly [protein phosphatase 1](/details-go/GO:0008157) ([Link](https://doi.org/10.1016/j.bbrc.2009.11.123)). In line with its role in regulating transcription factors and signaling cascades, the protein is primarily located in the [nucleus](/details-go/GO:0005634) and [nucleoplasm](/details-go/GO:0005654). ## Research Directions Evidence linking [SH3RF2](/details-gene/153769) to oncogenesis, specifically through the stabilization of the PAK4 protein, highlights a critical area for investigation ([Link](https://doi.org/10.1093/carcin/bgt338)). This finding, combined with its high expression in epithelial tissues that are common origins for cancers (e.g., breast, colon), suggests its homeostatic functions may be hijacked during malignant transformation. Based on the available data, several testable hypotheses can be proposed: 1. Given its high and specific significance in [ventricular cardiac muscle cell](/details-cell/CL2000046) and its documented interaction with protein phosphatase 1, [SH3RF2](/details-gene/153769) may function as a key regulator of cardiac muscle contractility or the response to hypertrophic stress by ubiquitinating specific substrates involved in calcium signaling or phosphorylation-dependent pathways. 2. The high expression of [SH3RF2](/details-gene/153769) in multiple epithelial cell types ([luminal epithelial cell of mammary gland](/details-cell/CL0002326), [colon epithelial cell](/details-cell/CL0011108)) and its published role as an oncogene ([Link](https://doi.org/10.1093/carcin/bgt338)) suggest that its E3 ligase activity may be co-opted during tumorigenesis to degrade tumor suppressors or stabilize oncoproteins, thereby promoting cell survival and proliferation in epithelial-derived cancers. To test the second hypothesis, a multi-pronged approach could be employed. First, one could generate stable [SH3RF2](/details-gene/153769) knockout and over-expression cell lines using CRISPR-Cas9 and lentiviral vectors in non-transformed mammary and colon epithelial cells. Changes in proliferation, [positive regulation of cell migration](/details-go/GO:0030335), and [negative regulation of apoptotic process](/details-go/GO:0043066) could then be assessed using standard in vitro assays. Subsequently, performing immunoprecipitation followed by mass spectrometry (IP-MS) in relevant cancer cell lines (e.g., MCF-7, HT-29) would help identify novel ubiquitination substrates of [SH3RF2](/details-gene/153769), providing a direct mechanistic link to its pro-tumorigenic functions. From a therapeutic perspective, [SH3RF2](/details-gene/153769) represents a potential target for cancer therapy, where inhibition of its E3 ligase activity would be the primary strategy. The development of small molecule inhibitors that block its catalytic RING domain or disrupt substrate binding could destabilize its oncogenic client proteins, such as PAK4. However, the high significance of [SH3RF2](/details-gene/153769) in cardiac muscle cells suggests a potential risk for cardiotoxicity, necessitating the development of highly specific inhibitors or targeted delivery systems to achieve a favorable therapeutic window.

Genular Protein ID: 289968751

Symbol: SH3R2_HUMAN

Name: E3 ubiquitin-protein ligase SH3RF2

UniProtKB Accession Codes:

Q8TEC5 A8K961 Q08AM9 Q6GMR9 Q8N5S8 Q96LP8

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 4 CTD 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EC 1 EMBL 10 Ensembl 2 GO 15 Gene3D 2 GeneCards 1 GeneTree 1 GenomeRNAi 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 10 KEGG 1 MANE-Select 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PRINTS 1 PRO 1 PROSITE 3 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 4 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 3 RNAct 1 RefSeq 4 SIGNOR 1 SMART 2 SMR 1 STRING 1 SUPFAM 2 SignaLink 1 TopDownProteomics 1 TreeFam 1 UCSC 1 UniPathway 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 19945436

Title: FLJ23654 encodes a heart protein phosphatase 1-binding protein (Hepp1).

PubMed ID: 19945436

DOI: 10.1016/j.bbrc.2009.11.123

PubMed ID: 14702039

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

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 15372022

Title: The DNA sequence and comparative analysis of human chromosome 5.

PubMed ID: 15372022

DOI: 10.1038/nature02919

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: 19807924

Title: Identification of SH3 domain interaction partners of human FasL (CD178) by phage display screening.

PubMed ID: 19807924

DOI: 10.1186/1471-2172-10-53

PubMed ID: 19389623

Title: Docking motif-guided mapping of the interactome of protein phosphatase-1.

PubMed ID: 19389623

DOI: 10.1016/j.chembiol.2009.02.012

PubMed ID: 20696164

Title: POSH2 is a RING finger E3 ligase with Rac1 binding activity through a partial CRIB domain.

PubMed ID: 20696164

DOI: 10.1016/j.febslet.2010.07.060

PubMed ID: 22128169

Title: Sh3rf2/POSHER protein promotes cell survival by RING-mediated proteasomal degradation of the c-Jun N-terminal kinase scaffold POSH (Plenty of SH3s) protein.

PubMed ID: 22128169

DOI: 10.1074/jbc.m111.269431

PubMed ID: 24130170

Title: SH3RF2 functions as an oncogene by mediating PAK4 protein stability.

PubMed ID: 24130170

DOI: 10.1093/carcin/bgt338

Sequence Information:

  • Length: 729
  • Mass: 79320
  • Checksum: F85CCC0188DA8477
  • Sequence:
    • MDDLTLLDLL ECPVCFEKLD VTAKVLPCQH TFCKPCLQRV FKAHKELRCP ECRTPVFSNI 
EALPANLLLV RLLDGVRSGQ SSGRGGSFRR PGTMTLQDGR KSRTNPRRLQ ASPFRLVPNV 
RIHMDGVPRA KALCNYRGQN PGDLRFNKGD IILLRRQLDE NWYQGEINGI SGNFPASSVE 
VIKQLPQPPP LCRALYNFDL RGKDKSENQD CLTFLKDDII TVISRVDENW AEGKLGDKVG 
IFPILFVEPN LTARHLLEKN KGRQSSRTKN LSLVSSSSRG NTSTLRRGPG SRRKVPGQFS 
ITTALNTLNR MVHSPSGRHM VEISTPVLIS SSNPSVITQP MEKADVPSSC VGQVSTYHPA 
PVSPGHSTAV VSLPGSQQHL SANMFVALHS YSAHGPDELD LQKGEGVRVL GKCQDGWLRG 
VSLVTGRVGI FPNNYVIPIF RKTSSFPDSR SPGLYTTWTL STSSVSSQGS ISEGDPRQSR 
PFKSVFVPTA IVNPVRSTAG PGTLGQGSLR KGRSSMRKNG SLQRPLQSGI PTLVVGSLRR 
SPTMVLRPQQ FQFYQPQGIP SSPSAVVVEM GSKPALTGEP ALTCISRGSE AWIHSAASSL 
IMEDKEIPIK SEPLPKPPAS APPSILVKPE NSRNGIEKQV KTVRFQNYSP PPTKHYTSHP 
TSGKPEQPAT LKASQPEAAS LGPEMTVLFA HRSGCHSGQQ TDLRRKSALG KATTLVSTAS 
GTQTVFPSK

Genular Protein ID: 59212424

Symbol: Q08AM8_HUMAN

Name: N/A

UniProtKB Accession Codes:

Q08AM8

Database IDs:

ARBA 7 AlphaFoldDB 1 BioGRID-ORCS 1 CDD 4 CTD 1 ChiTaRS 1 DNASU 1 DisGeNET 1 EMBL 2 GO 7 Gene3D 2 IntAct 1 InterPro 10 KEGG 1 NCBI Taxonomy 1 OrthoDB 1 PANTHER 2 PRINTS 1 PROSITE 5 PROSITE-ProRule 2 PeptideAtlas 1 Pfam 4 PharmGKB 1 RefSeq 1 SAM 1 SMART 2 SUPFAM 2

Citations:

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

Sequence Information:

  • Length: 729
  • Mass: 79324
  • Checksum: 8EE48B18141DE913
  • Sequence:
    • MDDLTLLDLL ECPVCFEKLD VTAKVLPCQH TFCKPCLQRV FKAHKELRCP ECRTPVFSNI 
EALPANLLLV RLLDGVRSGQ SSGRGGSFRR PGTMTLQDGR KSRTNPRRLQ ASPFRLVPNV 
RIHMDGVPRA KALCNYRGQN PGDLRFNKGD IILLRRQLDE NWYQGEINGI SGNFPASSVE 
VIKQLPQPPP LCRALYNFDL RGKDKSENQD CLTFLKDDII TVISRVDENW AEGKLGDKVG 
IFPILFVEPN LTARHLLEKN KGRQSSRTKN LSLVSSSSRG NTSTLRRGPG SRRKVPGQFS 
ITTALNTLNR MVHSPSGRHM VEISTPVLIS SSNPSVITQP MEKADVPSSC VGQVSTYHPA 
PVSPGHSTAV VSLPGSQQHL SANMFVALHS YSAHGPDELD LQKGEGVRVL GKCQDGWLRG 
VSLVTGRVGI FPNNYVIPIF RKTSSFPDSR SPGLYTTWTL STSSVSSQGS ISEGDPRQSR 
PFKSVFVPTA IVNPVRSTAG PGTLGQGSLR KGRSSMRKNG SLQRPLQSGI PTLVVGSLRR 
SPTMVLRPQQ FQFYQPQGIP SSPSAVVVEM GSKPALTGEP AFTCISRGSE ARIHSAASSL 
IMEDKEIPIK SEPLPKPPAS APPSILVKPE NSRNGIEKQV KTVRFQNYSP PPTKHYTSHP 
TSGKPEQPAT LKASQPEAAS LGPEMTVLFA HRSGCHSGQQ TDLRRKSALG KATTLVSTAS 
GTQTVFPSK