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RHOBTB3 (Rho-related BTB domain containing 3)

Written2016-04Shuo Cai, Francisco Rivero
Cardiff China Medical Research Collaborative Institute of Cancer and Genetics, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, (SC); Centre for Cardiovascular and Metabolic Research, The Hull York Medical School, University of Hull, Cottingham Road, Hull HU6 7RX, (FR) UK. CaiS5@cardiff.ac.uk; francisco.rivero@hyms.ac.uk

Abstract RHOBTB3 is one of the three members of the RhoBTB family. All RhoBTB proteins are characterized by a GTPase domain followed by a proline-rich region, a tandem of two BTB domains and a C-terminal putative RING finger domain. In RHOBTB3 the GTPase domain has ATPase activity. RHOBTB3 is a putative tumour suppressor gene. Expression of RHOBTB3 has been found significantly decreased in the breast, kidney, uterus, lung, and ovary tumors and in human renal carcinomas. The mechanism of RHOBTB3 protein as a tumor suppressor may be related to its function as an adaptor of cullin 3-dependent ubiquitin ligases. RHOBTB3 targets cyclin E for degradation and facilitates entry into the G2 phase of the cell cycle. RHOBTB3 also builds a multiprotein complex that maintains HIFα (hypoxia inducible factor α) levels low by promoting its hydroxylation, ubiquitination and degradation.

Keywords tumor suppressor, ubiquitin ligase, cullin 3, HIFα, cyclin E

(Note : for Links provided by Atlas : click)

Identity

Alias_namesRho-related BTB domain containing 3
Alias_symbol (synonym)KIAA0878
Other alias
HGNC (Hugo) RHOBTB3
LocusID (NCBI) 22836
Atlas_Id 43467
Location 5q15  [Link to chromosome band 5q15]
Location_base_pair Starts at 95066850 and ends at 95132071 bp from pter ( according to hg19-Feb_2009)  [Mapping RHOBTB3.png]

DNA/RNA

 
  Gene structure of RHOBTB3. Boxes represent exons. The coding region is represented in blue.
Description The RHOBTB3 gene spans over 65 Kbp genomic DNA and consists of 12 exons. The first exon splits the translation initiation codon (Figure 1). The coding sequence of RHOBTB3 is 1833 nucleotides long (Ramos et al., 2002).
Transcription There is no evidence of transcription variants.

Protein

Note RHOBTB3 is one of the three members of the RhoBTB family in vertebrates. The RhoBTB family was identified during the study of the genes encoding Rho-related proteins in the lower eukaryote Dictyostelium discoideum (Rivero et al., 2002). All three RhoBTB proteins may be implicated in tumorigenesis (Berthold et al., 2008b).
 
  Architecture of RhoBTB proteins. The figure shows the three human (Hs) RhoBTB subfamily members as well as the Drosophila (Dm) and Dictyostelium (Dd) orthologues. The simplified phylogenetic tree on the left illustrates the relationship among the proteins (overall percentage similarity between branches). The different domains are indicated with colours.
Description RHOBTB3 is 611 amino acids long. All RhoBTB proteins share the same domain architecture: a GTPase domain is followed by a proline-rich region, a tandem of two BTB domains and a C-terminal region (Figure 2). The GTPase domain of RHOBTB3 is considerably divergent and unlike the GTPase domain of RHOBTB1 and RHOBTB2, which bind GTP, it binds and hydrolyses ATP (Espinosa et al., 2009).
The proline-rich region links the GTPase to the first BTB domain. In RHOBTB1 and RHOBTB2 this region could act as a SH3 domain-binding site, however in RhoBTB3 the proline-rich region is not very prominent.
The BTB domain (broad complex, tramtrack and bric-a-brac) is an evolutionary conserved protein-protein interaction domain that participates in homomeric and heteromeric associations with other BTB domains. The BTB domain was also identified as a component of multimeric cullin 3-dependent ubiquitin ligase complexes. The first BTB domain is bipartite, being interrupted by an insertion of unknown function that is much shorter in RhoBTB3 than in the two other members of the family. The BTB domains of RhoBTB allow the formation of homodimers and of heterodimers with other proteins of the RhoBTB family (Berthold et al., 2008).
The C-terminus is a region conserved in all members of the RhoBTB subfamily. It predictably folds as 4 consecutive alpha-helices and one beta-strand and may constitute a RING finger domain (Manjarrez et al., 2014). Many RING finger domains function as ubiquitin ligases. RHOBTB3 bears a CAAX motif that is typical for classical Rho GTPases. This motif undergoes isoprenylation of the cysteine residue and proteolytic cleavage of the last three residues and serves for localization of the protein to membranes, although it's not the only determinant for the Golgi apparatus targeting of RHOBTB3 (Lu and Pfeffer, 2013).
Expression RHOBTB3 is ubiquitously expressed, with high mRNA levels present in placenta, testis, pancreas, adrenal and salivary glands and neural and cardiac tissues. It is also expressed in fetal tissues (Ramos et al., 2002; Nagase et al., 1998).
Expression of the mouse Rhobtb3 gene has been investigated in great detail in a gene trap mouse strain that expresses β-galactosidase under the control of the endogenous Rhobtb3 promoter (Lutz et al., 2014). Histochemical detection of β-galactosidase expression revealed a profile characterized by nearly ubiquitous expression of Rhobtb3 in the embryo, with particularly high levels in bone, cartilage, all types of muscle, testis and restricted areas of the nervous system. In the adult mouse expression declines considerably, but persists at low levels in cardiac muscle, the tunica media of blood vessels, the muscularis of hollow organs and cartilage, and at high levels in the seminiferous tubules and peripheral nerves.
Expression of RHOBTB3 has been found decreased in kidney, breast, uterus, lung and ovary tumors in a cancer profiling array (Berthold et al., 2008) and in diverse renal cell carcinoma subtypes (Zhang et al., 2015).
Localisation The localisation of endogenous RHOBTB3 has not been investigated. Available antibodies fail to recognise any endogenous RHOBTB3 in fixed cells and tissues. In cells expressing epitope tagged RHOBTB3 ectopically the protein tends to form aggregates in a paranuclear pattern (Berthold et al., 2008). When expressed at moderate levels RHOBTB3 displays a vesicular pattern predominantly surrounding the centrosome. RHOBTB3 co-localises with Golgi apparatus markers. Some vesicles co-localize with early endosome markers or in close vicinity to microtubules or stress fibres (Berthold et al., 2008; Espinosa et al., 2009).
Function Following functions have been proposed for RHOBTB3. The molecular mechanisms by which RhoBTB3 exerts those roles are beginning to be elucidated and in most cases may be related to its role in ubiquitination.
1. RHOBTB3 as adaptor of cullin 3-dependent ubiquitin ligases.
The first BTB domain binds to the N-terminal region of CUL3 (cullin 3), but not other cullins. RHOBTB3 is itself a substrate for the cullin 3-based ubiquitin ligase complex (Berthold et al., 2008). RhoBTB proteins appear to exist in an inactive state through an intramolecular interaction of the BTB domain region with the GTPase domain (Berthold et al., 2008).
Several potential substrates of RHOBTB3-dependent ubiquitin ligase complex have been described, including LRRC41 (MUF-1) and cyclin E and RHOBTB3 also participates in the degradation of HIF1A (HIFα hypoxia inducible factor α). They have implications in tumorigenesis and are described below.
RHOBTB3 also interacts with the 5-HT7a receptor, the most common splice variant of HTR7, the serotonin receptor 7. This receptor is involved in a wide variety of pathophysiological processes of the central nervous system. Interestingly, the 5-HT7a receptor appears to interact with cullin 3 independently of RHOBTB3, and RHOBTB3 apparently inhibits proteasomal degradation of the receptor (Mathys et al., 2012)
2. RHOBTB3 roles in cell cycle regulation and tumorigenesis.
RHOBTB3, like RHOBTB1 and RHOBTB2, interacts with MUF1 (LLRC41, leucine rich repeat containing 41). MUF1 is a nuclear protein and carries a BC-box that functions as a linker in multicomponent cullin 5-dependent ubiquitin ligase complexes (Schenkov et al., 2012). MUF1 may be a substrate for RhoBTB-Cullin 3 ubiquitin ligase complexes. The function of MUF1 is unknown, but it is suspected to be involved in the DNA damage response.
RHOBTB3 binds cyclin E1 (CCNE1) (and to a lesser extent CCNB1 (cyclin B1)), uncoupled from its dependent kinaseCDK2. Cyclin E regulates the cell cycle transition from G1 to S phase and is degraded before entry into G2 phase. RHOBTB3 targets cyclin E for ubiquitination by a cullin 3-dependent ubiquitin ligase that localizes at the Golgi apparatus (Lu and Pfeffer, 2013). RhoBTB3 protein accumulates during the S phase after the plateau of cyclin E. Depletion of RHOBTB3 causes S-phase arrest in cultured cells accompanied by increased levels of cyclin E and increased activity of CDK2. Therefore RHOBTB3 regulates the S/G2 transition of the cell cycle by targeting cyclin E for ubiquitination. The RHOBTB3-CUL3 pathway constitutes an alternative ubiquitination route to the KITLG (SCF)- FBXW7 pathway, but these two pathways may target different pools of cyclin E. This mechanism may contribute to the role of RHOBTB3 as a tumor suppressor. Deregulation of cyclin E levels can have a significant impact on cell proliferation, as shown in a significant percentage of breast cancers where high cyclin E correlates with tumor stage and grade.
Regulation of HIFα levels constitutes another case of cross-talk between different ubiquitination pathways. HIFs are key regulators of adaptive responses to low oxygen concentration. In the presence of oxygen their α-subunits are rapidly degraded through an ubiquitination-dependent proteasomal pathway after hydroxylation. Under hypoxia conditions HIFs accumulate and bind to hypoxia responsive elements of various genes, in many cases related to aspects of cancer growth. In fact, aberrant accumulation or activation of HIFs is closely linked to many types of cancer. Hydroxylated HIFα is targeted for ubiquitination by the von Hippel-Lindau (VHL) protein, a component of a CUL2 (cullin 2)-dependent ubiquitin ligase (Tanimoto et al., 2000).
RHOBTB3 acts as a scaffold for a multicomponent complex that regulates the degradation of HIFα. RHOBTB3 binds the prolyl hydroxylase EGLN1 (PHD2) that promotes hydroxylation of HIFα (Zhang et al., 2015). The complex also binds VHL protein and facilitates ubiquitination of HIFα. Additionally RHOBTB3 appears to heterodimerize with LIMD1, an adaptor for PHD2 and VHL, and this interaction enhances the activity of the complex. The chaperone HSP90AA1 (Hsp90) is incorporated to the complex through interaction with HIFα and does not seem to interact with RHOBTB3. Hsp90 may contribute to relieve the autoinhibitory conformation of RHOBTB3, as it has been proposed for RHOBTB2 (Manjarrez et al., 2014). Hypoxia reduces the formation of the RHOBTB3-dependent multicomponent complex, resulting in an accumulation of HIFα.
A tumor suppressor role for RHOBTB3 has been shown in xenograft experiments with Ras-transformed embryonic fibroblasts isolated from Rhobtb3 deficient mice or HeLa cells in which Rhobtb3 was silenced. The xenografts were larger and had increased levels of HIFα and its gene targets. It has been proposed that RHOBTB3 inhibits tumorigenesis by maintaining low HIFα levels and consequently suppressing the Warburg effect (Zhang et al., 2015).
3. RHOBTB3 and vesicle trafficking.
RHOBTB3 is a component of a complex required for retrograde transport to the Golgi complex that contains RAB9A and the cargo selection protein PLIN3 (TIP47), with which RHOBTB3 interacts (Espinosa et al., 2009). When RHOBTB3 is depleted by gene silencing the Golgi apparatus becomes fragmented (Lu and Pfeffer 2013) and the mannose-6-P receptor adopts a disperse localization in Rab9 positive vesicles, indicative of altered retrograde transport, but endocytosis and exocytosis are not changed (Espinosa et al., 2009). A model has been proposed in which Rab9 on vesicles travelling from late endosomes to the Golgi relieves the autoinhibitory conformation of RHOBTB3 and allows maximal ATP hydrolysis. Activation of RHOBTB3 releases TIP47, facilitating vesicle uncoating and membrane fusion (Pfeffer 2009).
4. Other roles.
A case of a male carrying a balanced paracentric inversion of chromosome 5 that disrupts RHOBTB3 has been reported. This patient showed asymmetric leg growth and large hands and behavior problems. It hasn't been determined whether disruption of RHOBTB3 is the cause of those alterations (Chen et al., 2010).
The characterization of a gene trap knockout mouse strain has shown that disruption of the Rhobtb3 gene causes reduced perinatal viability, a postnatal growth defect that persists in males after weaning and reduced testis size (Lutz et al., 2014). Ablation of Rhobtb3 only caused very modest changes in the pattern of gene expression of adult heart and brain. Lack of Rhobtb3 did not affect the rate of proliferation of primary lung fibroblasts isolated from 10-week-old animals (Lutz et al., 2014) but higher proliferation rates have been reported in mouse embryonic fibroblasts (Zhang et al., 2015).
RHOBTB3 has been identified as a candidate blood biomarker for hallucinations. Gene expression was found decreased in high hallucination states (Kurian et al., 2011). RHOBTB3 has also been proposed as a candidate vulnerability gene for Alzheimer's disease (Miller et al., 2013).
Like other members of the RhoBTB family, RHOBTB3 has no apparent influence on cell morphology and actin organization (Berthold et al., 2008).
Homology There are three RhoBTB proteins in vertebrates: RHOBTB1, RHOBTB2 and RhOBTB3 (Figure 2). RHOBTB2 is very similar to RHOBTB1, while RHOBTB3 displays very low similarity to these. Orthologues have been found in amoebae and in insects but they are absent in plants and fungi.

Mutations

Note No pathogenic mutations have been identified to date.

Implicated in

Note
  
Entity Various cancers, including kidney, breast, uterus, lung and ovary
Note Expression of RHOBTB3 was found moderately but significantly decreased in breast, kidney, uterus, lung, and ovary tumour samples in a cancer profiling array. The decrease affected to 80% of kidney and to 56% of breast cancer samples. The expression changes correlated with those of CUL3 in the same samples (Berthold et al., 2008)
  
  
Entity Renal cell carcinoma
Note RHOBTB3 expression is significantly decreased in clear cell renal cell carcinoma, papillary renal cell carcinoma, hereditary clear cell renal cell carcinoma and non-hereditary clear cell renal cell carcinoma subtypes (Zhang et al., 2015).
  

Bibliography

Rho GTPases of the RhoBTB subfamily and tumorigenesis
Berthold J, Schenkova K, Rivero F
Acta Pharmacol Sin 2008 Mar;29(3):285-95
PMID 18298893
 
Breakpoint analysis of balanced chromosome rearrangements by next-generation paired-end sequencing
Chen W, Ullmann R, Langnick C, Menzel C, Wotschofsky Z, Hu H, Döring A, Hu Y, Kang H, Tzschach A, Hoeltzenbein M, Neitzel H, Markus S, Wiedersberg E, Kistner G, van Ravenswaaij-Arts CM, Kleefstra T, Kalscheuer VM, Ropers HH
Eur J Hum Genet 2010 May;18(5):539-43
PMID 19953122
 
RhoBTB3: A Rho GTPase-family ATPase required for endosome to Golgi transport.
Espinosa E, Calero M, Sridevi K, Pfeffer S.
Cell 2009; 137: 938-948.
PMID 19490898
 
RhoBTB3: a Rho GTPase-family ATPase required for endosome to Golgi transport
Espinosa EJ, Calero M, Sridevi K, Pfeffer SR
Cell 2009 May 29;137(5):938-48
PMID 19490898
 
Identification of blood biomarkers for psychosis using convergent functional genomics
Kurian SM, Le-Niculescu H, Patel SD, Bertram D, Davis J, Dike C, Yehyawi N, Lysaker P, Dustin J, Caligiuri M, Lohr J, Lahiri DK, Nurnberger JI Jr, Faraone SV, Geyer MA, Tsuang MT, Schork NJ, Salomon DR, Niculescu AB
Mol Psychiatry 2011 Jan;16(1):37-58
PMID 19935739
 
[Clinical significance of the disorders of hydrolysis and disaccharide absorption in the small intestine]
Levin AA
Klin Med (Mosk) 1974;52(8):33-7
PMID 4608665
 
Golgi-associated RhoBTB3 targets cyclin E for ubiquitylation and promotes cell cycle progression
Lu A, Pfeffer SR
J Cell Biol 2013 Oct 28;203(2):233-50
PMID 24145166
 
Expression analysis of mouse Rhobtb3 using a LacZ reporter and preliminary characterization of a knockout strain
Lutz J, Grimm-Gü EM, Joshi P, Rivero F
Histochem Cell Biol 2014 Nov;142(5):511-28
PMID 24923387
 
Hsp90-Dependent Assembly of the DBC2/RhoBTB2-Cullin3 E3-Ligase Complex.
Manjarrez J, Sun L, Prince T, Matts R.
PLoS ONE 2014; 9: e90054.
PMID 24608665
 
RhoBTB3 interacts with the 5-HT7a receptor and inhibits its proteasomal degradation
Matthys A, Van Craenenbroeck K, Lintermans B, Haegeman G, Vanhoenacker P
Cell Signal 2012 May;24(5):1053-63
PMID 22245496
 
Genes and pathways underlying regional and cell type changes in Alzheimer's disease
Miller JA, Woltjer RL, Goodenbour JM, Horvath S, Geschwind DH
Genome Med 2013 May 25;5(5):48
PMID 23705665
 
Prediction of the coding sequences of unidentified human genes
Nagase T, Ishikawa K, Suyama M, Kikuno R, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O
XI The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro
PMID 9872452
 
Multiple routes of protein transport from endosomes to the trans Golgi network.
Pfeffer S.
FEBS Lett 2009; 583: 3811-3816.
PMID 19879268
 
Multiple routes of protein transport from endosomes to the trans Golgi network
Pfeffer SR
FEBS Lett 2009 Dec 3;583(23):3811-6
PMID 19879268
 
Genomic organization and expression profile of the small GTPases of the RhoBTB family in human and mouse
Ramos S, Khademi F, Somesh BP, Rivero F
Gene 2002 Oct 2;298(2):147-57
PMID 12426103
 
The Dictyostelium discoideum family of Rho-related proteins
Rivero F, Dislich H, Glöckner G, Noegel AA
Nucleic Acids Res 2001 Mar 1;29(5):1068-79
PMID 11222756
 
MUF1/Leucine-rich repeat containing 41 (LRRC41), a substrate of RhoBTB-dependent cullin 3 ubiquitin ligase complexes, is a predominantly nuclear dimeric protein.
Schenkov K, Lutz J, Kopp M, Ramos S, Rivero F.
J Mol Biol 2012; 422: 659-673.
PMID 22709582
 
MUF1/leucine-rich repeat containing 41 (LRRC41), a substrate of RhoBTB-dependent cullin 3 ubiquitin ligase complexes, is a predominantly nuclear dimeric protein
Schenková K, Lutz J, Kopp M, Ramos S, Rivero F
J Mol Biol 2012 Oct 5;422(5):659-73
PMID 22709582
 
Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein
Tanimoto K, Makino Y, Pereira T, Poellinger L
EMBO J 2000 Aug 15;19(16):4298-309
PMID 10944113
 
RHOBTB3 promotes proteasomal degradation of HIF? through facilitating hydroxylation and suppresses the Warburg effect.
Zhang C, Liu Q, Li M, Lin S, Peng Y, Wu D, Li T, Fu Q, Jia W, Wang X, Ma Y, Cui J, Pu C, Lian G, Guo H, Ye Z, Lin S.
Cell Res 2015, 25: 1025-1042.
PMID 26215701
 
RHOBTB3 promotes proteasomal degradation of HIFα through facilitating hydroxylation and suppresses the Warburg effect
Zhang CS, Liu Q, Li M, Lin SY, Peng Y, Wu D, Li TY, Fu Q, Jia W, Wang X, Ma T, Zong Y, Cui J, Pu C, Lian G, Guo H, Ye Z, Lin SC
Cell Res 2015 Sep;25(9):1025-42
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Citation

This paper should be referenced as such :
Cai S, Rivero F
RHOBTB3 (Rho-related BTB domain containing 3);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/RHOBTB3ID43467ch5q15.html


External links

Nomenclature
HGNC (Hugo)RHOBTB3   18757
Cards
AtlasRHOBTB3ID43467ch5q15
Entrez_Gene (NCBI)RHOBTB3  22836  Rho related BTB domain containing 3
Aliases
GeneCards (Weizmann)RHOBTB3
Ensembl hg19 (Hinxton)ENSG00000164292 [Gene_View]  chr5:95066850-95132071 [Contig_View]  RHOBTB3 [Vega]
Ensembl hg38 (Hinxton)ENSG00000164292 [Gene_View]  chr5:95066850-95132071 [Contig_View]  RHOBTB3 [Vega]
ICGC DataPortalENSG00000164292
TCGA cBioPortalRHOBTB3
AceView (NCBI)RHOBTB3
Genatlas (Paris)RHOBTB3
WikiGenes22836
SOURCE (Princeton)RHOBTB3
Genetics Home Reference (NIH)RHOBTB3
Genomic and cartography
GoldenPath hg19 (UCSC)RHOBTB3  -     chr5:95066850-95132071 +  5q15   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)RHOBTB3  -     5q15   [Description]    (hg38-Dec_2013)
EnsemblRHOBTB3 - 5q15 [CytoView hg19]  RHOBTB3 - 5q15 [CytoView hg38]
Mapping of homologs : NCBIRHOBTB3 [Mapview hg19]  RHOBTB3 [Mapview hg38]
OMIM607353   
Gene and transcription
Genbank (Entrez)AB020685 AF131794 AK023621 AK290034 BC013169
RefSeq transcript (Entrez)NM_014899
RefSeq genomic (Entrez)NC_000005 NC_018916 NT_034772 NW_004929323
Consensus coding sequences : CCDS (NCBI)RHOBTB3
Cluster EST : UnigeneHs.445030 [ NCBI ]
CGAP (NCI)Hs.445030
Alternative Splicing GalleryENSG00000164292
Gene ExpressionRHOBTB3 [ NCBI-GEO ]   RHOBTB3 [ EBI - ARRAY_EXPRESS ]   RHOBTB3 [ SEEK ]   RHOBTB3 [ MEM ]
Gene Expression Viewer (FireBrowse)RHOBTB3 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)22836
GTEX Portal (Tissue expression)RHOBTB3
Protein : pattern, domain, 3D structure
UniProt/SwissProtO94955   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtO94955  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProO94955
Splice isoforms : SwissVarO94955
PhosPhoSitePlusO94955
Domaine pattern : Prosite (Expaxy)BTB (PS50097)   
Domains : Interpro (EBI)BTB/POZ_dom    P-loop_NTPase    RhoBTB3    SKP1/BTB/POZ    Small_GTPase   
Domain families : Pfam (Sanger)BTB (PF00651)    Ras (PF00071)   
Domain families : Pfam (NCBI)pfam00651    pfam00071   
Domain families : Smart (EMBL)BTB (SM00225)  
Conserved Domain (NCBI)RHOBTB3
DMDM Disease mutations22836
Blocks (Seattle)RHOBTB3
SuperfamilyO94955
Human Protein AtlasENSG00000164292
Peptide AtlasO94955
HPRD09557
IPIIPI00007132   IPI00965631   IPI00967840   IPI00966320   IPI00968250   IPI00968037   IPI00967509   IPI00968093   IPI00966524   IPI00964245   IPI00966315   
Protein Interaction databases
DIP (DOE-UCLA)O94955
IntAct (EBI)O94955
FunCoupENSG00000164292
BioGRIDRHOBTB3
STRING (EMBL)RHOBTB3
ZODIACRHOBTB3
Ontologies - Pathways
QuickGOO94955
Ontology : AmiGOprotein binding  ATP binding  cytosol  small GTPase mediated signal transduction  metabolic process  ATPase activity  ATPase activity  Rab GTPase binding  trans-Golgi network membrane  retrograde transport, endosome to Golgi  extracellular exosome  
Ontology : EGO-EBIprotein binding  ATP binding  cytosol  small GTPase mediated signal transduction  metabolic process  ATPase activity  ATPase activity  Rab GTPase binding  trans-Golgi network membrane  retrograde transport, endosome to Golgi  extracellular exosome  
REACTOMEO94955 [protein]
REACTOME Pathways6811440 [pathway]   
NDEx NetworkRHOBTB3
Atlas of Cancer Signalling NetworkRHOBTB3
Wikipedia pathwaysRHOBTB3
Orthology - Evolution
OrthoDB22836
GeneTree (enSembl)ENSG00000164292
Phylogenetic Trees/Animal Genes : TreeFamRHOBTB3
HOVERGENO94955
HOGENOMO94955
Homologs : HomoloGeneRHOBTB3
Homology/Alignments : Family Browser (UCSC)RHOBTB3
Gene fusions - Rearrangements
Fusion : MitelmanRHOBTB3/CRNKL1 [5q15/20p11.23]  
Fusion Cancer (Beijing)cytochrome_b [RHOBTB3]  -  5q15 [FUSC002839]
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerRHOBTB3 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)RHOBTB3
dbVarRHOBTB3
ClinVarRHOBTB3
1000_GenomesRHOBTB3 
Exome Variant ServerRHOBTB3
ExAC (Exome Aggregation Consortium)RHOBTB3 (select the gene name)
Genetic variants : HAPMAP22836
Genomic Variants (DGV)RHOBTB3 [DGVbeta]
DECIPHER (Syndromes)5:95066850-95132071  ENSG00000164292
CONAN: Copy Number AnalysisRHOBTB3 
Mutations
ICGC Data PortalRHOBTB3 
TCGA Data PortalRHOBTB3 
Broad Tumor PortalRHOBTB3
OASIS PortalRHOBTB3 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICRHOBTB3  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDRHOBTB3
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch RHOBTB3
DgiDB (Drug Gene Interaction Database)RHOBTB3
DoCM (Curated mutations)RHOBTB3 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)RHOBTB3 (select a term)
intoGenRHOBTB3
NCG5 (London)RHOBTB3
Cancer3DRHOBTB3(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM607353   
Orphanet
MedgenRHOBTB3
Genetic Testing Registry RHOBTB3
NextProtO94955 [Medical]
TSGene22836
GENETestsRHOBTB3
Huge Navigator RHOBTB3 [HugePedia]
snp3D : Map Gene to Disease22836
BioCentury BCIQRHOBTB3
ClinGenRHOBTB3
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD22836
Chemical/Pharm GKB GenePA38679
Clinical trialRHOBTB3
Miscellaneous
canSAR (ICR)RHOBTB3 (select the gene name)
Probes
Litterature
PubMed23 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineRHOBTB3
EVEXRHOBTB3
GoPubMedRHOBTB3
iHOPRHOBTB3
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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