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Protein

Rho family-interacting cell polarization regulator 2

Gene

RIPOR2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Acts as an inhibitor of the small GTPase RHOA and plays several roles in the regulation of myoblast and hair cell differentiation, lymphocyte T proliferation and neutrophil polarization (PubMed:17150207, PubMed:24687993, PubMed:23241886, PubMed:24958875, PubMed:25588844, PubMed:27556504). Inhibits chemokine-induced T lymphocyte responses, such as cell adhesion, polarization and migration (PubMed:23241886). Involved also in the regulation of neutrophil polarization, chemotaxis and adhesion (By similarity). Required for normal development of inner and outer hair cell stereocilia within the cochlea of the inner ear (By similarity). Plays a role for maintaining the structural organization of the basal domain of stereocilia (By similarity). Involved in mechanosensory hair cell function (By similarity). Required for normal hearing (PubMed:24958875).By similarity5 Publications
Isoform 2: Acts as an inhibitor of the small GTPase RHOA (PubMed:25588844). Plays a role in fetal mononuclear myoblast differentiation by promoting filopodia and myotube formation (PubMed:17150207). Maintains naive T lymphocytes in a quiescent state (PubMed:27556504).3 Publications

Miscellaneous

Cells lacking isoform 2 exhibit a severe reduction of myotube formation. In contrast, isoform 2 overexpression induces formation of filopodia.

GO - Molecular functioni

  • 14-3-3 protein binding Source: UniProtKB
  • identical protein binding Source: Ensembl

GO - Biological processi

  • auditory receptor cell stereocilium organization Source: Ensembl
  • cellular response to chemokine Source: UniProtKB
  • cellular response to mechanical stimulus Source: Ensembl
  • establishment of protein localization Source: Ensembl
  • negative regulation of cell adhesion Source: UniProtKB
  • negative regulation of establishment of T cell polarity Source: UniProtKB
  • negative regulation of protein localization to cell leading edge Source: UniProtKB
  • negative regulation of Rho guanyl-nucleotide exchange factor activity Source: UniProtKB
  • negative regulation of Rho protein signal transduction Source: UniProtKB
  • negative regulation of T cell migration Source: UniProtKB
  • negative regulation of T cell proliferation Source: UniProtKB
  • positive regulation of cell cycle arrest Source: UniProtKB
  • positive regulation of filopodium assembly Source: UniProtKB
  • positive regulation of myoblast differentiation Source: UniProtKB
  • positive regulation of myoblast fusion Source: UniProtKB
  • positive regulation of neutrophil chemotaxis Source: UniProtKB
  • positive regulation of neutrophil extravasation Source: UniProtKB
  • protein homooligomerization Source: Ensembl
  • regulation of establishment of cell polarity Source: UniProtKB
  • regulation of mitotic spindle assembly Source: UniProtKB
  • sensory perception of sound Source: UniProtKB
  • skeletal muscle fiber development Source: InterPro

Keywordsi

Molecular functionDevelopmental protein, Signal transduction inhibitor
Biological processCell adhesion, Chemotaxis, Differentiation, Hearing, Myogenesis

Names & Taxonomyi

Protein namesi
Recommended name:
Rho family-interacting cell polarization regulator 2
Gene namesi
Name:RIPOR2
Synonyms:C6orf32, DIFF48, FAM65B, KIAA0386, PL481 Publication
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 6

Organism-specific databases

HGNCiHGNC:13872. RIPOR2.

Subcellular locationi

Isoform 1 :
Isoform 2 :
  • Cytoplasm 1 Publication

  • Note: Accumulates at the leading edge of polarized neutrophils in a chemokine-dependent manner (PubMed:25588844).1 Publication

GO - Cellular componenti

  • apical plasma membrane Source: Ensembl
  • cytoplasm Source: UniProtKB
  • cytoskeleton Source: UniProtKB
  • filopodium Source: UniProtKB
  • mitochondrion Source: UniProtKB-SubCell
  • stereocilium Source: UniProtKB
  • stereocilium membrane Source: UniProtKB-SubCell

Keywords - Cellular componenti

Cell membrane, Cell projection, Cytoplasm, Cytoskeleton, Membrane

Pathology & Biotechi

Involvement in diseasei

Deafness, autosomal recessive, 104 (DFNB104)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information.
See also OMIM:616515

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi21S → A: Reduces phosphorylation, interaction with HDAC6, YWHAB and 14-3-3 proteins, localization at the front of the neutrophil upon chemokine stimulation and prevents T cell proliferation inhibition; when associated with A-37; A-341; A-523 and A-585 (isoform 2). 2 Publications1
Mutagenesisi37S → A: Reduces phosphorylation, interaction with HDAC6, YWHAB and 14-3-3 proteins, localization at the front of the neutrophil upon chemokine stimulation and prevents T cell proliferation inhibition; when associated with A-21; A-341; A-523 and A-585 (isoform 2). 2 Publications1
Mutagenesisi151 – 152RL → AA: Inhibits interaction with RHOA and does not prevent T cell proliferation inhibition; in isoform 2. 2 Publications2
Mutagenesisi155 – 156GA → RR: Inhibits interaction with RHOA; in isoform 2. 2 Publications2
Mutagenesisi341S → A: Reduces phosphorylation, interaction with HDAC6, YWHAB and 14-3-3 proteins, localization at the front of the neutrophil upon chemokine stimulation and prevents T cell proliferation inhibition; when associated with A-21; A-37; A-523 and A-585 (isoform 2). 2 Publications1
Mutagenesisi523S → A: Reduces phosphorylation, interaction with HDAC6, YWHAB and 14-3-3 proteins, localization at the front of the neutrophil upon chemokine stimulation and prevents T cell proliferation inhibition; when associated with A-21; A-37; A-341 and A-585 (isoform 2). 2 Publications1
Mutagenesisi585S → A: Reduces phosphorylation, interaction with HDAC6, YWHAB and 14-3-3 proteins, localization at the front of the neutrophil upon chemokine stimulation and prevents T cell proliferation inhibition; when associated with A-21; A-37; A-341 and A-523 (isoform 2). 2 Publications1

Keywords - Diseasei

Deafness, Non-syndromic deafness

Organism-specific databases

DisGeNETi9750.
MalaCardsiFAM65B.
MIMi616515. phenotype.
OpenTargetsiENSG00000111913.
Orphaneti90636. Autosomal recessive non-syndromic sensorineural deafness type DFNB.
PharmGKBiPA162387677.

Polymorphism and mutation databases

BioMutaiFAM65B.
DMDMi296439477.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002891141 – 1068Rho family-interacting cell polarization regulator 2Add BLAST1068

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei21Phosphoserine; in isoform 21 Publication1
Modified residuei37Phosphoserine; in isoform 21 Publication1
Modified residuei341Phosphoserine; in isoform 21 Publication1
Modified residuei523Phosphoserine; in isoform 21 Publication1
Modified residuei573PhosphoserineBy similarity1
Modified residuei585Phosphoserine; in isoform 21 Publication1

Post-translational modificationi

Phosphorylated. Isoform 2 is phosphorylated in T cells (PubMed:27556504). Chemokine-induced phosphorylation of isoform 2 in neutrophils occurs in a PKC- and AKT-dependent manner, resulting in RIPOR2 interaction with YWHAB and stabilization (PubMed:25588844). Isoform 2 is phosphorylated by PKCA, AKT1 and MAPKAPK1A; in vitro (PubMed:25588844).2 Publications
Asn-41 was reported to be N-glycosylated; however as this position is probably not extracellular, the in vivo relevance is not proven (PubMed:16335952). Acetylated during myogenic differentiation (PubMed:24687993).2 Publications

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiQ9Y4F9.
PaxDbiQ9Y4F9.
PeptideAtlasiQ9Y4F9.
PRIDEiQ9Y4F9.

PTM databases

iPTMnetiQ9Y4F9.
PhosphoSitePlusiQ9Y4F9.

Expressioni

Tissue specificityi

Expressed in primary fetal mononuclear myoblast (PubMed:17150207). Expressed strongly in naive T lymphocytes (PubMed:27556504). Expressed weakly in activated T lymphocytes (at protein level) (PubMed:27556504). Expressed in blood cells and adult tissues of hematopoietic origin, such as the secondary lymphoid organs (PubMed:23241886). Expressed in cytotrophoblast (PubMed:9055809).4 Publications

Inductioni

Up-regulated during fetal mononuclear myoblast differentiation (PubMed:17150207, PubMed:24687993). Up-regulated during cytotrophoblast differentiation (PubMed:9055809). Up-regulated during granulocyte differentiation (PubMed:9055809). Isoform 1 and isoform 2 are down-regulated in T lymphocytes upon T-cell antigen receptor (TCR) stimulation (PubMed:27556504). Isoform 1 and isoform 2 are up-regulated by FOXO1 (PubMed:23241886).5 Publications

Gene expression databases

BgeeiENSG00000111913.
CleanExiHS_FAM65B.
ExpressionAtlasiQ9Y4F9. baseline and differential.
GenevisibleiQ9Y4F9. HS.

Interactioni

Subunit structurei

Homooligomer; homooligomerization is regulated by RHOC and leads to the formation of concatemers through the association of N- and C-termini (By similarity). Interacts with 14-3-3 proteins; these interactions occur during myogenic cell differentiation (PubMed:24687993). Interacts with HDAC6; this interaction occurs during early myogenic differentiation and prevents HDAC6 to deacetylate tubulin (PubMed:24687993). Interacts with DYSF; this interaction occurs during early myogenic differentiation (PubMed:24687993). Interacts with MYOF (PubMed:24687993). Interacts with RHOC (By similarity). Isoform 1 and isoform 2 interact (via active GTP- or inactive GDP-bound forms) with RHOA; these interactions are direct, block the loading of GTP to RHOA and decrease upon chemokine CCL19 stimulation in primary T lymphocytes (PubMed:23241886, PubMed:25588844). Isoform 2 interacts (phosphorylated form) with HDAC6; this interaction induces T cell proliferation arrest (PubMed:27556504). Isoform 2 interacts (phosphorylated form) with 14-3-3 proteins; these interactions induces T cell proliferation arrest (PubMed:27556504). Isoform 2 interacts with 14-3-3 proteins (PubMed:25588844). Isoform 2 interacts (via phosphorylated form) with YWHAB; this interaction occurs in a chemokine-dependent manner and does not compete for binding of RIPOR2 with RHOA nor blocks inhibition of RIPOR2-mediated RHOA activity (PubMed:25588844). Isoform 2 interacts with YWHAE (PubMed:25588844). Isoform 2 interacts with YWHAQ (PubMed:25588844).By similarity4 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • 14-3-3 protein binding Source: UniProtKB
  • identical protein binding Source: Ensembl

Protein-protein interaction databases

BioGridi115098. 9 interactors.
IntActiQ9Y4F9. 10 interactors.
STRINGi9606.ENSP00000259698.

Structurei

3D structure databases

ProteinModelPortaliQ9Y4F9.
SMRiQ9Y4F9.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni55 – 113Involved in cell filopodia formation1 PublicationAdd BLAST59

Coiled coil

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Coiled coili83 – 112Sequence analysisAdd BLAST30
Coiled coili768 – 793Sequence analysisAdd BLAST26

Sequence similaritiesi

Belongs to the RIPOR family.Curated

Keywords - Domaini

Coiled coil

Phylogenomic databases

eggNOGiENOG410IEN6. Eukaryota.
ENOG410XR7R. LUCA.
GeneTreeiENSGT00490000043360.
HOGENOMiHOG000112476.
HOVERGENiHBG053834.
InParanoidiQ9Y4F9.
OMAiHFREKAL.
OrthoDBiEOG091G018M.
PhylomeDBiQ9Y4F9.
TreeFamiTF329332.

Family and domain databases

Gene3Di1.25.10.10. 1 hit.
InterProiView protein in InterPro
IPR011989. ARM-like.
IPR016024. ARM-type_fold.
IPR026136. FAM65.
IPR031780. FAM65_N.
IPR033035. FAM65B.
PANTHERiPTHR15829. PTHR15829. 1 hit.
PTHR15829:SF18. PTHR15829:SF18. 1 hit.
PfamiView protein in Pfam
PF15903. PL48. 1 hit.
SUPFAMiSSF48371. SSF48371. 1 hit.

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q9Y4F9-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MLVGSQSFSP GGPNGIIRSQ SFAGFSGLQE RRSRCNSFIE NSSALKKPQA
60 70 80 90 100
KLKKMHNLGH KNNNPPKEPQ PKRVEEVYRA LKNGLDEYLE VHQTELDKLT
110 120 130 140 150
AQLKDMKRNS RLGVLYDLDK QIKTIERYMR RLEFHISKVD ELYEAYCIQR
160 170 180 190 200
RLQDGASKMK QAFATSPASK AARESLTEIN RSFKEYTENM CTIEVELENL
210 220 230 240 250
LGEFSIKMKG LAGFARLCPG DQYEIFMKYG RQRWKLKGKI EVNGKQSWDG
260 270 280 290 300
EETVFLPLIV GFISIKVTEL KGLATHILVG SVTCETKELF AARPQVVAVD
310 320 330 340 350
INDLGTIKLN LEITWYPFDV EDMTASSGAG NKAAALQRRM SMYSQGTPET
360 370 380 390 400
PTFKDHSFFR WLHPSPDKPR RLSVLSALQD TFFAKLHRSR SFSDLPSLRP
410 420 430 440 450
SPKAVLELYS NLPDDIFENG KAAEEKMPLS LSFSDLPNGD CALTSHSTGS
460 470 480 490 500
PSNSTNPEIT ITPAEFNLSS LASQNEGMDD TSSASSRNSL GEGQEPKSHL
510 520 530 540 550
KEEDPEEPRK PASAPSEACR RQSSGAGAEH LFLENDVAEA LLQESEEASE
560 570 580 590 600
LKPVELDTSE GNITKQLVKR LTSAEVPMAT DRLLSEGSVG GESEGCRSFL
610 620 630 640 650
DGSLEDAFNG LLLALEPHKE QYKEFQDLNQ EVMNLDDILK CKPAVSRSRS
660 670 680 690 700
SSLSLTVESA LESFDFLNTS DFDEEEDGDE VCNVGGGADS VFSDTETEKH
710 720 730 740 750
SYRSVHPEAR GHLSEALTED TGVGTSVAGS PLPLTTGNES LDITIVRHLQ
760 770 780 790 800
YCTQLVQQIV FSSKTPFVAR SLLEKLSRQI QVMEKLAAVS DENIGNISSV
810 820 830 840 850
VEAIPEFHKK LSLLSFWTKC CSPVGVYHSP ADRVMKQLEA SFARTVNKEY
860 870 880 890 900
PGLADPVFRT LVSQILDRAE PLLSSSLSSE VVTVFQYYSY FTSHGVSDLE
910 920 930 940 950
SYLSQLARQV SMVQTLQSLR DEKLLQTMSD LAPSNLLAQQ EVLRTLALLL
960 970 980 990 1000
TREDNEVSEA VTLYLAAASK NQHFREKALL YYCEALTKTN LQLQKAACLA
1010 1020 1030 1040 1050
LKILEATESI KMLVTLCQSD TEEIRNVASE TLLSLGEDGR LAYEQLDKFP
1060
RDCVKVGGRH GTEVATAF
Length:1,068
Mass (Da):118,519
Last modified:May 18, 2010 - v4
Checksum:iCCA7DEB3A66F36AA
GO
Isoform 2 (identifier: Q9Y4F9-2) [UniParc]FASTAAdd to basket
Also known as: PL481 Publication

The sequence of this isoform differs from the canonical sequence as follows:
     360-409: Missing.
     641-641: C → K
     642-1068: Missing.

Show »
Length:591
Mass (Da):65,692
Checksum:iAB43802AF3D551EC
GO

Sequence cautioni

The sequence AAC51134 differs from that shown. Reason: Frameshift at several positions.Curated
The sequence BAA20840 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti13P → A in AAC51134 (PubMed:9055809).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_032572145A → G. Corresponds to variant dbSNP:rs11967003Ensembl.1
Natural variantiVAR_032573320V → M1 PublicationCorresponds to variant dbSNP:rs35331811Ensembl.1
Natural variantiVAR_032574424E → K. Corresponds to variant dbSNP:rs34016544Ensembl.1
Natural variantiVAR_032575452S → C. Corresponds to variant dbSNP:rs34298086Ensembl.1
Natural variantiVAR_032576495E → K. Corresponds to variant dbSNP:rs35514577Ensembl.1
Natural variantiVAR_032577520R → C. Corresponds to variant dbSNP:rs35780910Ensembl.1
Natural variantiVAR_062193868R → Q1 PublicationCorresponds to variant dbSNP:rs9461073Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_025904360 – 409Missing in isoform 2. 2 PublicationsAdd BLAST50
Alternative sequenceiVSP_025905641C → K in isoform 2. 2 Publications1
Alternative sequenceiVSP_025906642 – 1068Missing in isoform 2. 2 PublicationsAdd BLAST427

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U49187 mRNA. Translation: AAC51134.1. Frameshift.
AB002384 mRNA. Translation: BAA20840.2. Different initiation.
AL512428, AL078584 Genomic DNA. Translation: CAH73086.2.
AL512428, AL078584 Genomic DNA. Translation: CAH73087.2.
AL078584, AL512428 Genomic DNA. Translation: CAI19934.2.
AL078584, AL512428 Genomic DNA. Translation: CAI19935.2.
CH471087 Genomic DNA. Translation: EAW55470.1.
BC001232 mRNA. Translation: AAH01232.1.
CCDSiCCDS47383.1. [Q9Y4F9-1]
CCDS47384.1. [Q9Y4F9-2]
RefSeqiNP_001273375.1. NM_001286446.2.
NP_001273376.1. NM_001286447.1.
NP_055537.2. NM_014722.4. [Q9Y4F9-1]
NP_056948.2. NM_015864.3. [Q9Y4F9-2]
XP_016867015.1. XM_017011526.1. [Q9Y4F9-2]
XP_016867016.1. XM_017011527.1. [Q9Y4F9-2]
UniGeneiHs.559459.
Hs.737906.

Genome annotation databases

EnsembliENST00000259698; ENSP00000259698; ENSG00000111913. [Q9Y4F9-1]
ENST00000378023; ENSP00000367262; ENSG00000111913. [Q9Y4F9-2]
ENST00000613507; ENSP00000482957; ENSG00000111913. [Q9Y4F9-1]
GeneIDi9750.
KEGGihsa:9750.
UCSCiuc003neo.3. human. [Q9Y4F9-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.

Entry informationi

Entry nameiRIPR2_HUMAN
AccessioniPrimary (citable) accession number: Q9Y4F9
Secondary accession number(s): A6NHP2
, Q13529, Q5VV37, Q5VV38, Q9BQ28
Entry historyiIntegrated into UniProtKB/Swiss-Prot: May 29, 2007
Last sequence update: May 18, 2010
Last modified: June 7, 2017
This is version 122 of the entry and version 4 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 6
    Human chromosome 6: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. SIMILARITY comments
    Index of protein domains and families