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REPS2 (RALBP1 associated Eps domain containing 2)

Written2010-06Salvatore Corallino, Luisa Castagnoli
Department of Biology, University of Rome Tor Vergata, via ricerca scientifica, 00133 Rome, Italy

(Note : for Links provided by Atlas : click)

Identity

Alias_symbol (synonym)POB1
Other alias
HGNC (Hugo) REPS2
LocusID (NCBI) 9185
Atlas_Id 44120
Location Xp22.2  [Link to chromosome band Xp22]
Location_base_pair Starts at 16946691 and ends at 17153280 bp from pter ( according to hg19-Feb_2009)  [Mapping REPS2.png]
Local_order Forward strand: before 16804550-16862642 CXorf15 (ENSG00000086712) and after 17300683-17301216. Known pseudogene RP11-674N8.1 (ENSG00000214321).
Fusion genes
(updated 2016)
LAP3 (4p15.32) / REPS2 (Xp22.2)MGP (12p12.3) / REPS2 (Xp22.2)MOSPD2 (Xp22.2) / REPS2 (Xp22.2)
REPS2 (Xp22.2) / TXLNG (Xp22.2)SHROOM2 (Xp22.2) / REPS2 (Xp22.2)
Note This gene is a member of the human CCDS set: CCDS14180, CCDS43919.

DNA/RNA

Description 18 exons in REPS2/POB1 gene.
Transcription The transcript length of REPS2/POB1 is 7945 bp. REPS2 is not differentially expressed in monozygotic twins. Northern blot analysis reveal strong expression in rat cerebrum, cerebellum, lung, and testis, with weak expression in kidney and no expression in heart, thymus, liver, spleen, or adrenal gland. Relatively highly expressed in androgen-dependent as compared to androgen-independent prostate cancer cell lines. REPS2/POB1 is down-regulated during progression of prostate cancer.

Protein

 
  REPS2/POB1: synopsis of protein structure, interactors, functions.
Description REPS2/POB1, Swiss-Prot Q8NFH8, is expressed as two isoforms, the short isoform is 521 residues long, while the 660 residues one differs by having a 139 amino acid extension at the amino-terminus. The most prominent structural/functional features, which are common to both isoforms, include an amino-terminal EH (Eps15 homology) domain, a central region containing two adjacent proline-rich regions and a carboxy-terminal portion mediating the binding to RalBP1. In the figure (not in scale), are described the main motifs and domains of the long isoform of REPS2/POB1, the interacting proteins and the cellular functions, that are described in the text.
Expression The POB1 mRNA is expressed in cerebrum, cerebellum, lung, weakly in kidney, and testis (Ikeda et al., 1998). It is relatively highly expressed in androgen-dependent as compared to androgen-independent prostate cancer cell lines and xenografts and it is down-regulated during progression of prostate cancer (Oosterhoff et al., 2003).
Localisation REPS2/POB1 localizes in the cytosol, in different sub cellular compartments: it colocalizes with clathrin CHC in coated pits, with CD63 in late endosomes, with GM130 in golgi and with LAMP2 in lysosomes. Localization is not EGF dependent and POB1 doesn't localize with EEA1 in early endosomes (Tomassi et al., 2008).
Function REPS2/POB1 is part of a protein complex that regulates the endocytosis and down regulation of growth factor receptors. Its expression can negatively affect growth factor signaling. Multiple transcript variants encoding different isoforms have been found for this gene and posttranslational modifications have been described, such as phosphorylation of Ser493 and Ser549 (Oppermann et al., 2009). The REPS2/POB1 has two amino-terminal EH domains. The structure of the second EH domain that extends from 265 to 367 has been solved by NMR and consists of two EF-hand structures, and the second one binds a calcium ion (Koshiba et al., 1999). The EH domain binds epsin, Eps15 and NF-kappaB p65, and it is associated to endocytosis and apoptosis. The central proline rich region of POB1/REPS2 binds to 14-3-3, amphiphysin II and Grb2 and it is associated to receptor downregulation and signaling. The carbossi-terminal proline rich binds PAG2 and influences paxillin localization in focal adhesion. POB1 C-terminus (514-660) directly interacts with a GTPase activating protein that functions downstream of the small G protein Ral, RalBP1. Their interaction induces apoptosis.

REPS2 downregulates receptor signaling and endocytosis: REPS2/POB1 interacts with Eps15, epsin EPN1, 14-3-3 isoforms, Grb2, amphiphysin
The presence of EH domains in REPS2/POB1 is symptomatic of a role of this gene in receptor endocytosis. In fact, REPS2/POB1 EH domain binds to Eps15 and to epsin that are both proteins present in clathrin-coated pits, involved in receptor endocytosis and receptor down regulation. The EH domain interacts specifically with the three Asn-Pro-Phe (NPF) motifs in the C-terminal region of epsin and their binding regulates receptor-mediated endocytosis (Morinaka et al., 1999).
Augmented expression of full-length POB1 in A431 cells does not affect either binding or internalization of EGF, on the contrary, over-expression of either the EH domain or the C-terminal region of REPS2/POB1 affects the ligand dependent internalization pathway of EGF and insulin without interfering with the constitutive transferrin pathway (Nakashima et al., 1999).
Santonico et al. have demonstrated that the EH domain of REPS2/POB1 binds Eps15 through an unconventional recognition specificity, since it binds to both NPF and DPF (Asp-Prp-Phe) motifs. The region of Eps15 responsible for the interaction with the EH domain of REPS2/POB1 maps within a 18 amino acid peptide (residues 623-640) that includes three DPF repeats. Accordingly, the authors identify a cluster of solvent exposed Lys residues, which are only found in the EH domain of REPS2/POB1, and influence binding to both NPF and DPF motifs (Santonico et al., 2007).
RalBP1, REPS2/POB1, epsin, and Eps15 form a complex with alpha-adaptin of AP-2 in Chinese hamster ovary cells and this complex is reduced in mitotic phase, when REPS2/POB1 and epsin are found phosphorylated. They are both phosphoryated by p34 cdc2 kinase, in vitro. POB1 is found phosphorylated in Ser551 and Ser493, in vivo. Phosphorylation of epsin in Ser 357 inhibits binding to POB1, causing disassembly of the complex, thus inhibiting receptor mediated endocytosis (Kariya et al., 2000). This data explains the contribution of the EH domain of POB1 to the formation of a protein complex that favours receptor internalization and that it is dismantled in mitosis. It is suggested that EGF stimulation induces also tyrosine-phosphorylation of POB1 and subsequent formation of a EGFR-POB1 complex in COS cells (Ikeda et al., 1998).
REPS2/POB1 shorter isoform2 is downregulated during human prostate cancer progression from androgen-dependent to androgen-independent (Oosterhoff et al., 2003). It was observed that a high level of REPS2 correlates with reduced EGF-internalisation and signaling since the induced expression of REPS2 exerts an inhibiting effect on several EGF-responsive genes (EGF-receptor, EGR-1, Fos and Jun) (Oosterhoff et al., 2005). Accordingly, increased expression of POB1 isoform 2 correlates with a decrease of EGF-induced phosphorylation of Erk1-Erk2 and Shc (Tomassi et al., 2008). From these experiments, it can be concluded that increased REPS2/POB1 expression negatively affects EGF receptor internalisation and subsequent signaling. Therefore, the decreased REPS2 expression observed during prostate cancer progression, results in enhanced EGF receptor expression and signaling, which could add to the androgen-independent state of advanced prostate cancer.
The central region of REPS2/POB1 plays a regulatory role in epidermal growth factor receptor endocytosis and signaling. Overexpression of the central region of POB1 (447-504), inhibits EGF endocytosis, titrating essential proteins away, thus depauperating the receptor down-regulation machinery. In fact, this region of POB1/REPS2 plays its regulatory role in EGFR endocytosis by binding: (i) to 14-3-3 proteins in a phosphorylation dependent way (i.e., phospho-Ser493 of POB1), (ii) to the C-SH3 domain of Grb2 and (iii) to the SH3 of amphiphysin II. The target of the SH3 domain of amphiphysin and of the carboxy-terminal SH3 of Grb2 is a short peptide flanking Arg483 in POB1. These interactions are not EGF dependent and are probably exclusive, since the binding motifs are only nine amino acids apart. These findings suggest that 14-3-3 could work by bridging the EGF receptor and the scaffold protein POB1/REPS2. The 14-3-3 binding motif HSRASSLD, flanking the Ser493 of POB1, is conserved in the mouse orthologs and in the 14-3-3 binding motif that flanks the Ser510 of human REPS1 protein, found phosphorylated in vivo in A431 cells (Stover DR et al. Phosphosite). The POB1 Ser493 is predicted to be phosphorylated by Akt. In agreement, when cells are treated with PI3K/Akt inhibitor wortmannin, 14-3-3 binding to REPS2/POB1 is abolished (Tomassi et al., 2008). The 14-3-3 zeta has already been reported as associating with the EGFR, epidermal growth factor receptor, cytoplasmic tail and co-localizing along the plasma membrane with EGFR upon EGF stimulation (Jin et al., 2004). Thus a 14-3-3 dimer could bridge REPS2/POB1 to the EGFR upon EGF induction.

Cell migration and paxillin localization: REPS2/POB1 antagonises PAG2/ASAP1
POB1 forms a complex with PAG2/ASAP1 in intact cells. PAG2 is a paxillin-associated protein with ADP-ribosylation factor GTPase-activating protein activity, also called ASAP1 (ArfGAP with SH3 domain, ankyrin repeat and PH domain UniProtKB: Q9ULH1). The SH3 of PAG2 binds the proline motif (562PSKPIR567) at the carboxyl-terminal region of POB1. This motif is essential for PAG2-POB1 interaction since substitution of the two proline residues with alanines in mutant POB1(PA), impaired its binding to PAG2. POB1 may therefore form a complex with paxillin through PAG2. Paxillin is a focal adhesion-associated scaffolding protein that recruits signaling molecules to the focal adhesions and forms protein complexes that coordinate signaling, cell spreading and motility. PAG2 overexpression causes loss of endogenous paxillin recruitment to focal contacts and also impaires cell migratory activities. The ability to suppress fibronectin-dependent migration depends on the ArfGAP domain of PAG2, but not on the POB1-binding domain, of PAG2. On the other end, POB1, but not POB1(PA), can suppress the inhibitory action of PAG2 on paxillin localization to focal adhesion (Oshiro et al., 2002). These results suggest that POB1, by binding to PAG2, suppresses the inhibitory action of PAG2 on the paxillin recruitment to focal contacts. This suggests that POB1 may function as a scaffold protein that interacts with proteins involved in endocytosis and migration, thus regulating signaling and motility. PAG2/ASAP1 gene was found associated with prostate cancer metastasis since it is up-regulated in a human metastatic prostate subline and immunohistochemistry of xenograft sections show a significantly strong cytoplasmic ASAP1 protein staining in tumor-nonmetastatic PCa2 tissue, compared to a non-staining in benign tissue, and an even stronger staining in PCa1-metastatic tissue. Moreover, additional ASAP1 gene copies are detected in 58% of the primary prostate cancer clinical specimens. A small interfering RNA reducing ASAP1 protein expression, can suppress in vitro PC-3 cell migration and matrigel invasion. Therefore PAG2/ASAP1 represents a therapeutic target and a biomarker for metastatic disease (Lin et al., 2008) while REPS2/POB1 can suppress PAG2 oncogenic-metastatic activity.

Mutations

Somatic - S324F, cds mutation 971C>T heterozygous in glioblastoma multiforme (Parsons et al., 2008).
- V67M, cds mutation 199G>A homozygous in malignant melanoma.
- No high level gene amplification (>7), 1 homozygous deletion in breast cancer, 559 LOH (Loss of Heterozygosity).

Implicated in

Note
  
Entity Non-small cell lung cancer (NSLC) and prostate cancer
Note - Apoptosis in non-small cell lung cancer (NSLC) and prostate cancer: REPS2 binds and inhibits RalBP1.
Ikeda et al. (1998) cloned POB1 (partner of Ralbp1) as the first known binding partner of Ralbp1 by the yeast two-hybrid method using Ralbp1/RLIP76 as bait and clearly demonstrated specific binding and complex formation between Ralbp1 and REPS2/POB1. The binding to RalBP1 did not affect the GTPase activating activity of RalBP1. The interaction of POB1 with RalBP1 induces cell death in human prostate cancer cell ines LNCaP-FGC and LNCaP-LNO. Oosterhoff et al. show that REPS2/POB1-induces apoptosis in 45% of transfected cells, within 48 hours. When prostate cancer cell lines are transfected with a deletion mutant of REPS2/POB1, lacking the RalBP1 binding domain, only 30-40% of the transfected cells became apoptotic after 72-96 hours (Oosterhoff et al., 2003).
REPS2/POB1 (514-660) binds RalBP1 C-terminal amino acids, 499-655, while an almost overlapping region of RalBP1 (440-655) binds the heat shock factor 1 Hsf-1 (Hu and Mivechi, 2003). Shingal et al. show a ternary complex formation between RalBP1, Hsf-1, and REPS2/POB1. RalBP1, Hsf1, HSP90 and tubulin make a complex in cell (Singhal et al., 2008). Hsf-1 and REPS2/POB1 induce drug sensitivity and apoptosis by inhibiting RalBP1.
Binding of REPS2/POB1 to RALBP1 inhibits the transport activity of the Ral-binding nucleotidase, which functions as an energy-dependent transporter for GSH-conjugates as well as unrelated xenobiotics. RALBP1 (RLIP76) is the major transporter of the anthracycline antibiotic, doxorubicin, which is one of the most widely used anticancer drugs (Singhal et al., 2007). Therefore, REPS2/POB1 is a specific and saturable inhibitor of the glutathione-electrophile conjugates and of the doxorubicin transport activity of RalBP1. Yadav et al. show that REPS2/POB1 can regulate the transport function of RalBP1/RLIP76 and, in agreement with previous studies, show that inhibition of RalBP1 induces apoptosis in cancer cells through the accumulation of endogenously formed GSH-conjugates (Yadav et al., 2005). Hence, REPS2/POB1 over-expression inhibits RalBP1-mediated transport of glutathione-conjugates thus promoting apoptosis and can influence drug-efflux mechanisms that cause resistance to cancer treatment. Hsf-1 also causes specific and saturable inhibition of the transport activity of RalBP1. The combined augmentation of Hsf-1 and REPS2/POB1 causes nearly complete inhibition of RalBP1 and a dramatic apoptosis in NSLC (non-small cell lung cancer) cell line H358 through Ralbp1 binding (Singhal et al., 2008). The marked apoptotic effect caused by the increase of Hsf-1 and REPS2/POB1 in lung cancer cells, suggests a novel targeted therapy in which liposomally encapsulated Hsf-1 and POB1 could be used clinically as a therapeutic agent.

- Apoptosis in prostate cancer cells: REPS2/POB1 counteracts the apoptosis inhibitor NF-kappaB p65
The NF-kappaB subunit p65 is identified as a human REPS2/POB1 protein partner, since the NPF-motif in p65 acts as binding site for the EH domain in REPS2. However, in cultured prostate cancer cells, the REPS2-p65 interaction is triggered upon stimulation with the phorbol ester, phorbol-12-myristate-13-acetate (PMA). During prostate cancer progression from androgen-dependent to androgen-independent growth, the observed downregulation of REPS2 is accompanied by upregulation of NF-kappaB activity, that inhibits apoptosis (Penninkhof et al., 2004). Hence, the authors suggest that a decreased expression of REPS2 might be a key factor in causing prostate cancer cells to avoid apoptosis.

  
  
Entity Breast cancer
Note Doolan et al. (2009) suggest that REPS2 mRNAs may be useful as favourable prognostic and predictive markers for breast cancer. Univariate and multivariate analyses were used to identify associations between expression of these transcripts and patients' clinicopathological and survival data.
  

Bibliography

TMEM25, REPS2 and Meis 1: favourable prognostic and predictive biomarkers for breast cancer.
Doolan P, Clynes M, Kennedy S, Mehta JP, Germano S, Ehrhardt C, Crown J, O'Driscoll L.
Tumour Biol. 2009;30(4):200-9. Epub 2009 Sep 21.
PMID 19776672
 
HSF-1 interacts with Ral-binding protein 1 in a stress-responsive, multiprotein complex with HSP90 in vivo.
Hu Y, Mivechi NF.
J Biol Chem. 2003 May 9;278(19):17299-306. Epub 2003 Mar 5.
PMID 12621024
 
Identification and characterization of a novel protein interacting with Ral-binding protein 1, a putative effector protein of Ral.
Ikeda M, Ishida O, Hinoi T, Kishida S, Kikuchi A.
J Biol Chem. 1998 Jan 9;273(2):814-21.
PMID 9422736
 
Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization.
Jin J, Smith FD, Stark C, Wells CD, Fawcett JP, Kulkarni S, Metalnikov P, O'Donnell P, Taylor P, Taylor L, Zougman A, Woodgett JR, Langeberg LK, Scott JD, Pawson T.
Curr Biol. 2004 Aug 24;14(16):1436-50.
PMID 15324660
 
Regulation of complex formation of POB1/epsin/adaptor protein complex 2 by mitotic phosphorylation.
Kariya K, Koyama S, Nakashima S, Oshiro T, Morinaka K, Kikuchi A.
J Biol Chem. 2000 Jun 16;275(24):18399-406.
PMID 10764745
 
Solution structure of the Eps15 homology domain of a human POB1 (partner of RalBP1).
Koshiba S, Kigawa T, Iwahara J, Kikuchi A, Yokoyama S.
FEBS Lett. 1999 Jan 15;442(2-3):138-42.
PMID 9928989
 
ASAP1, a gene at 8q24, is associated with prostate cancer metastasis.
Lin D, Watahiki A, Bayani J, Zhang F, Liu L, Ling V, Sadar MD, English J, Fazli L, So A, Gout PW, Gleave M, Squire JA, Wang YZ.
Cancer Res. 2008 Jun 1;68(11):4352-9.
PMID 18519696
 
Epsin binds to the EH domain of POB1 and regulates receptor-mediated endocytosis.
Morinaka K, Koyama S, Nakashima S, Hinoi T, Okawa K, Iwamatsu A, Kikuchi A.
Oncogene. 1999 Oct 21;18(43):5915-22.
PMID 10557078
 
Small G protein Ral and its downstream molecules regulate endocytosis of EGF and insulin receptors.
Nakashima S, Morinaka K, Koyama S, Ikeda M, Kishida M, Okawa K, Iwamatsu A, Kishida S, Kikuchi A.
EMBO J. 1999 Jul 1;18(13):3629-42.
PMID 10393179
 
EGF signalling in prostate cancer cell lines is inhibited by a high expression level of the endocytosis protein REPS2.
Oosterhoff JK, Kuhne LC, Grootegoed JA, Blok LJ.
Int J Cancer. 2005 Feb 10;113(4):561-7.
PMID 15455380
 
Large-scale proteomics analysis of the human kinome.
Oppermann FS, Gnad F, Olsen JV, Hornberger R, Greff Z, Keri G, Mann M, Daub H.
Mol Cell Proteomics. 2009 Jul;8(7):1751-64. Epub 2009 Apr 15.
PMID 19369195
 
Interaction of POB1, a downstream molecule of small G protein Ral, with PAG2, a paxillin-binding protein, is involved in cell migration.
Oshiro T, Koyama S, Sugiyama S, Kondo A, Onodera Y, Asahara T, Sabe H, Kikuchi A.
J Biol Chem. 2002 Oct 11;277(41):38618-26. Epub 2002 Jul 30.
PMID 12149250
 
An integrated genomic analysis of human glioblastoma multiforme.
Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW.
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PMID 18772396
 
Identification of REPS2 as a putative modulator of NF-kappaB activity in prostate cancer cells.
Penninkhof F, Grootegoed JA, Blok LJ.
Oncogene. 2004 Jul 22;23(33):5607-15.
PMID 15184881
 
Binding to DPF-motif by the POB1 EH domain is responsible for POB1-Eps15 interaction.
Santonico E, Panni S, Falconi M, Castagnoli L, Cesareni G.
BMC Biochem. 2007 Dec 21;8:29.
PMID 18154663
 
Hsf-1 and POB1 induce drug sensitivity and apoptosis by inhibiting Ralbp1.
Singhal SS, Yadav S, Drake K, Singhal J, Awasthi S.
J Biol Chem. 2008 Jul 11;283(28):19714-29. Epub 2008 May 12.
PMID 18474607
 
The central proline rich region of POB1/REPS2 plays a regulatory role in epidermal growth factor receptor endocytosis by binding to 14-3-3 and SH3 domain-containing proteins.c
Tomassi L, Costantini A, Corallino S, Santonico E, Carducci M, Cesareni G, Castagnoli L.
BMC Biochem. 2008 Jul 22;9:21.
PMID 18647389
 
POB1 over-expression inhibits RLIP76-mediated transport of glutathione-conjugates, drugs and promotes apoptosis.
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PMID 15707977
 

Citation

This paper should be referenced as such :
Corallino, S ; Castagnoli, L
REPS2 (RALBP1 associated Eps domain containing 2)
Atlas Genet Cytogenet Oncol Haematol. 2011;15(3):288-292.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/REPS2ID44120chXp22.html


External links

Nomenclature
HGNC (Hugo)REPS2   9963
Cards
AtlasREPS2ID44120chXp22
Entrez_Gene (NCBI)REPS2  9185  RALBP1 associated Eps domain containing 2
AliasesPOB1
GeneCards (Weizmann)REPS2
Ensembl hg19 (Hinxton)ENSG00000169891 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000169891 [Gene_View]  chrX:16946691-17153280 [Contig_View]  REPS2 [Vega]
ICGC DataPortalENSG00000169891
TCGA cBioPortalREPS2
AceView (NCBI)REPS2
Genatlas (Paris)REPS2
WikiGenes9185
SOURCE (Princeton)REPS2
Genetics Home Reference (NIH)REPS2
Genomic and cartography
GoldenPath hg38 (UCSC)REPS2  -     chrX:16946691-17153280 +  Xp22.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)REPS2  -     Xp22.2   [Description]    (hg19-Feb_2009)
EnsemblREPS2 - Xp22.2 [CytoView hg19]  REPS2 - Xp22.2 [CytoView hg38]
Mapping of homologs : NCBIREPS2 [Mapview hg19]  REPS2 [Mapview hg38]
OMIM300317   
Gene and transcription
Genbank (Entrez)AB208937 AF010233 AF511533 AF512951 AI221053
RefSeq transcript (Entrez)NM_001080975 NM_004726
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)REPS2
Cluster EST : UnigeneHs.186810 [ NCBI ]
CGAP (NCI)Hs.186810
Alternative Splicing GalleryENSG00000169891
Gene ExpressionREPS2 [ NCBI-GEO ]   REPS2 [ EBI - ARRAY_EXPRESS ]   REPS2 [ SEEK ]   REPS2 [ MEM ]
Gene Expression Viewer (FireBrowse)REPS2 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)9185
GTEX Portal (Tissue expression)REPS2
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ8NFH8   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ8NFH8  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ8NFH8
Splice isoforms : SwissVarQ8NFH8
PhosPhoSitePlusQ8NFH8
Domaine pattern : Prosite (Expaxy)EF_HAND_1 (PS00018)    EF_HAND_2 (PS50222)    EH (PS50031)   
Domains : Interpro (EBI)EF-hand-dom_pair    EF_Hand_1_Ca_BS    EF_hand_dom    EH_dom   
Domain families : Pfam (Sanger)EF-hand_4 (PF12763)   
Domain families : Pfam (NCBI)pfam12763   
Domain families : Smart (EMBL)EH (SM00027)  
Conserved Domain (NCBI)REPS2
DMDM Disease mutations9185
Blocks (Seattle)REPS2
PDB (SRS)1IQ3   
PDB (PDBSum)1IQ3   
PDB (IMB)1IQ3   
PDB (RSDB)1IQ3   
Structural Biology KnowledgeBase1IQ3   
SCOP (Structural Classification of Proteins)1IQ3   
CATH (Classification of proteins structures)1IQ3   
SuperfamilyQ8NFH8
Human Protein AtlasENSG00000169891
Peptide AtlasQ8NFH8
HPRD02262
IPIIPI00382936   IPI00332687   IPI00973140   IPI00852723   IPI00909456   IPI00556669   
Protein Interaction databases
DIP (DOE-UCLA)Q8NFH8
IntAct (EBI)Q8NFH8
FunCoupENSG00000169891
BioGRIDREPS2
STRING (EMBL)REPS2
ZODIACREPS2
Ontologies - Pathways
QuickGOQ8NFH8
Ontology : AmiGOcalcium ion binding  protein binding  cytosol  protein complex assembly  epidermal growth factor receptor signaling pathway  membrane organization  
Ontology : EGO-EBIcalcium ion binding  protein binding  cytosol  protein complex assembly  epidermal growth factor receptor signaling pathway  membrane organization  
REACTOMEQ8NFH8 [protein]
REACTOME PathwaysR-HSA-8856828 [pathway]   
NDEx NetworkREPS2
Atlas of Cancer Signalling NetworkREPS2
Wikipedia pathwaysREPS2
Orthology - Evolution
OrthoDB9185
GeneTree (enSembl)ENSG00000169891
Phylogenetic Trees/Animal Genes : TreeFamREPS2
HOVERGENQ8NFH8
HOGENOMQ8NFH8
Homologs : HomoloGeneREPS2
Homology/Alignments : Family Browser (UCSC)REPS2
Gene fusions - Rearrangements
Fusion : MitelmanMGP/REPS2 [12p12.3/Xp22.2]  [t(X;12)(p22;p12)]  
Fusion : MitelmanREPS2/TXLNG [Xp22.2/Xp22.2]  [t(X;X)(p22;p22)]  
Fusion : MitelmanSHROOM2/REPS2 [Xp22.2/Xp22.2]  [t(X;X)(p22;p22)]  
Fusion: TCGAREPS2 Xp22.2 TXLNG Xp22.2 PRAD
Fusion: TCGASHROOM2 Xp22.2 REPS2 Xp22.2 BLCA
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerREPS2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)REPS2
dbVarREPS2
ClinVarREPS2
1000_GenomesREPS2 
Exome Variant ServerREPS2
ExAC (Exome Aggregation Consortium)REPS2 (select the gene name)
Genetic variants : HAPMAP9185
Genomic Variants (DGV)REPS2 [DGVbeta]
DECIPHERREPS2 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisREPS2 
Mutations
ICGC Data PortalREPS2 
TCGA Data PortalREPS2 
Broad Tumor PortalREPS2
OASIS PortalREPS2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICREPS2  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDREPS2
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
LOVD (Leiden Open Variation Database)X-chromosome gene database
BioMutasearch REPS2
DgiDB (Drug Gene Interaction Database)REPS2
DoCM (Curated mutations)REPS2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)REPS2 (select a term)
intoGenREPS2
NCG5 (London)REPS2
Cancer3DREPS2(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM300317   
Orphanet
MedgenREPS2
Genetic Testing Registry REPS2
NextProtQ8NFH8 [Medical]
TSGene9185
GENETestsREPS2
Target ValidationREPS2
Huge Navigator REPS2 [HugePedia]
snp3D : Map Gene to Disease9185
BioCentury BCIQREPS2
ClinGenREPS2
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD9185
Chemical/Pharm GKB GenePA34330
Clinical trialREPS2
Miscellaneous
canSAR (ICR)REPS2 (select the gene name)
Other databaseSANGER
Probes
Litterature
PubMed25 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineREPS2
EVEXREPS2
GoPubMedREPS2
iHOPREPS2
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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