ID   RHOH_HUMAN              Reviewed;         191 AA.
AC   Q15669;
DT   01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1997, sequence version 1.
DT   27-MAR-2024, entry version 209.
DE   RecName: Full=Rho-related GTP-binding protein RhoH;
DE   AltName: Full=GTP-binding protein TTF;
DE   AltName: Full=Translocation three four protein;
DE   Flags: Precursor;
GN   Name=RHOH; Synonyms=ARHH, TTF;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   PubMed=7784061;
RA   Dallery E., Galiegue-Zouitina S., Collyn-D'Hooghe M., Quief S., Denis C.,
RA   Hildebrand M.-P., Lantoine D., Deweindt C., Tilly H., Bastard C.,
RA   Kerckaert J.-P.;
RT   "TTF, a gene encoding a novel small G protein, fuses to the lymphoma-
RT   associated LAZ3 gene by t(3;4) chromosomal translocation.";
RL   Oncogene 10:2171-2178(1995).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA   Puhl H.L. III, Ikeda S.R., Aronstam R.S.;
RT   "cDNA clones of human proteins involved in signal transduction sequenced by
RT   the Guthrie cDNA resource center (www.cdna.org).";
RL   Submitted (APR-2002) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=B-cell;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [4]
RP   FUNCTION, INTERACTION WITH GDI1 AND GDI2, SUBCELLULAR LOCATION, INDUCTION,
RP   AND TISSUE SPECIFICITY.
RX   PubMed=11809807; DOI=10.1128/mcb.22.4.1158-1171.2002;
RA   Li X., Bu X., Lu B., Avraham H., Flavell R.A., Lim B.;
RT   "The hematopoiesis-specific GTP-binding protein RhoH is GTPase deficient
RT   and modulates activities of other Rho GTPases by an inhibitory function.";
RL   Mol. Cell. Biol. 22:1158-1171(2002).
RN   [5]
RP   INTERACTION WITH PAK5.
RX   PubMed=17064668; DOI=10.1016/j.bbrc.2006.09.172;
RA   Wu X., Frost J.A.;
RT   "Multiple Rho proteins regulate the subcellular targeting of PAK5.";
RL   Biochem. Biophys. Res. Commun. 351:328-335(2006).
RN   [6]
RP   FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND INDUCTION.
RX   PubMed=19414807; DOI=10.4049/jimmunol.0803846;
RA   Daryadel A., Yousefi S., Troi D., Schmid I., Schmidt-Mende J.,
RA   Mordasini C., Dahinden C.A., Ziemiecki A., Simon H.-U.;
RT   "RhoH/TTF negatively regulates leukotriene production in neutrophils.";
RL   J. Immunol. 182:6527-6532(2009).
RN   [7]
RP   FUNCTION, VARIANT EV4 38-TYR--PHE-191 DEL, AND CHARACTERIZATION OF VARIANT
RP   EV4 38-TYR--PHE-191 DEL.
RX   PubMed=22850876; DOI=10.1172/jci62949;
RA   Crequer A., Troeger A., Patin E., Ma C.S., Picard C., Pedergnana V.,
RA   Fieschi C., Lim A., Abhyankar A., Gineau L., Mueller-Fleckenstein I.,
RA   Schmidt M., Taieb A., Krueger J., Abel L., Tangye S.G., Orth G.,
RA   Williams D.A., Casanova J.L., Jouanguy E.;
RT   "Human RHOH deficiency causes T cell defects and susceptibility to EV-HPV
RT   infections.";
RL   J. Clin. Invest. 122:3239-3247(2012).
CC   -!- FUNCTION: Negative regulator of hematopoietic progenitor cell
CC       proliferation, survival and migration. Critical regulator of thymocyte
CC       development and T-cell antigen receptor (TCR) signaling by mediating
CC       recruitment and activation of ZAP70. Required for phosphorylation of
CC       CD3Z, membrane translocation of ZAP70 and subsequent activation of the
CC       ZAP70-mediated pathways. Essential for efficient beta-selection and
CC       positive selection by promoting the ZAP70-dependent phosphorylation of
CC       the LAT signalosome during pre-TCR and TCR signaling. Crucial for
CC       thymocyte maturation during DN3 to DN4 transition and during positive
CC       selection. Plays critical roles in mast cell function by facilitating
CC       phosphorylation of SYK in Fc epsilon RI-mediated signal transduction.
CC       Essential for the phosphorylation of LAT, LCP2, PLCG1 and PLCG2 and for
CC       Ca(2+) mobilization in mast cells (By similarity). Binds GTP but lacks
CC       intrinsic GTPase activity and is resistant to Rho-specific GTPase-
CC       activating proteins. Inhibits the activation of NF-kappa-B by TNF and
CC       IKKB and the activation of CRK/p38 by TNF. Inhibits activities of RAC1,
CC       RHOA and CDC42. Negatively regulates leukotriene production in
CC       neutrophils. {ECO:0000250, ECO:0000269|PubMed:11809807,
CC       ECO:0000269|PubMed:19414807, ECO:0000269|PubMed:22850876}.
CC   -!- SUBUNIT: Interacts with ZAP70 (via SH2 domains) and the interaction is
CC       enhanced by its phosphorylation by LCK. Interacts with SYK and the
CC       interaction is enhanced by its phosphorylation by FYN (By similarity).
CC       Interacts with GDI1 and GDI2. Interacts with PAK5 (By similarity).
CC       {ECO:0000250}.
CC   -!- INTERACTION:
CC       Q15669; Q8N9N5-2: BANP; NbExp=3; IntAct=EBI-1244971, EBI-11524452;
CC       Q15669; P51946: CCNH; NbExp=3; IntAct=EBI-1244971, EBI-741406;
CC       Q15669; Q86YD7: FAM90A1; NbExp=3; IntAct=EBI-1244971, EBI-6658203;
CC       Q15669; Q8NA54: IQUB; NbExp=3; IntAct=EBI-1244971, EBI-10220600;
CC       Q15669; O14713: ITGB1BP1; NbExp=3; IntAct=EBI-1244971, EBI-2127319;
CC       Q15669; Q63ZY3: KANK2; NbExp=3; IntAct=EBI-1244971, EBI-2556193;
CC       Q15669; O75431: MTX2; NbExp=3; IntAct=EBI-1244971, EBI-7415268;
CC       Q15669; Q6IQ23-2: PLEKHA7; NbExp=3; IntAct=EBI-1244971, EBI-12069346;
CC       Q15669; O94827-4: PLEKHG5; NbExp=3; IntAct=EBI-1244971, EBI-11980215;
CC       Q15669; Q0D2K3: RIPPLY1; NbExp=3; IntAct=EBI-1244971, EBI-10226430;
CC       Q15669; Q9BWG6: SCNM1; NbExp=3; IntAct=EBI-1244971, EBI-748391;
CC       Q15669; Q92673: SORL1; NbExp=3; IntAct=EBI-1244971, EBI-1171329;
CC       Q15669; P51687: SUOX; NbExp=3; IntAct=EBI-1244971, EBI-3921347;
CC       Q15669; Q9Y242: TCF19; NbExp=3; IntAct=EBI-1244971, EBI-7413767;
CC       Q15669; Q9NQW7-3: XPNPEP1; NbExp=3; IntAct=EBI-1244971, EBI-12079490;
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:11809807,
CC       ECO:0000269|PubMed:19414807}. Cell membrane {ECO:0000250}; Lipid-anchor
CC       {ECO:0000250}; Cytoplasmic side {ECO:0000250}. Note=Colocalizes
CC       together with ZAP70 in the immunological synapse. {ECO:0000250}.
CC   -!- TISSUE SPECIFICITY: Expressed only in hematopoietic cells. Present at
CC       very high levels in the thymus, less abundant in the spleen, and least
CC       abundant in the bone marrow. Expressed at a higher level in the TH1
CC       subtype of T-helper cells than in the TH2 subpopulation. Expressed in
CC       neutrophils under inflammatory conditions, such as cystic fibrosis,
CC       ulcerative colitis and appendicitis. {ECO:0000269|PubMed:11809807,
CC       ECO:0000269|PubMed:19414807}.
CC   -!- INDUCTION: By CSF2/GM-CSF. Down-regulated by phorbol myristate acetate
CC       (PMA). {ECO:0000269|PubMed:11809807, ECO:0000269|PubMed:19414807}.
CC   -!- DOMAIN: The region involved in interaction with ZAP70 is a non-
CC       canonical immunoreceptor tyrosine-based activation motif (ITAM).
CC       {ECO:0000250}.
CC   -!- PTM: Phosphorylated on tyrosine by LCK. Phosphorylated by FYN.
CC       Phosphorylation enhances the interactions with ZAP70 and SYK and is
CC       critical for its function in thymocyte development (By similarity).
CC       {ECO:0000250}.
CC   -!- DISEASE: Note=A chromosomal aberration involving RHOH is found in a
CC       non-Hodgkin lymphoma cell line. Translocation t(3;4)(q27;p11) with
CC       BCL6.
CC   -!- DISEASE: Epidermodysplasia verruciformis 4 (EV4) [MIM:618307]: A form
CC       of epidermodysplasia verruciformis, a rare genodermatosis associated
CC       with a high risk of skin carcinoma that results from an abnormal
CC       susceptibility to infection by specific human papillomaviruses,
CC       including the oncogenic HPV5. Infection leads to the early development
CC       of disseminated flat wart-like and pityriasis versicolor-like skin
CC       lesions. Cutaneous Bowen's carcinomas in situ and invasive squamous
CC       cell carcinomas develop in about half of the patients, mainly on sun-
CC       exposed skin areas. EV4 patients have decreased number of naive T
CC       cells, increased memory and effector T cells, and impaired T-cell
CC       receptor signaling. EV4 inheritance is autosomal recessive.
CC       {ECO:0000269|PubMed:22850876}. Note=The disease is caused by variants
CC       affecting the gene represented in this entry.
CC   -!- SIMILARITY: Belongs to the small GTPase superfamily. Rho family.
CC       {ECO:0000305}.
CC   -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC       Haematology;
CC       URL="https://atlasgeneticsoncology.org/gene/93/RHOH";
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DR   EMBL; Z35227; CAA84538.1; -; mRNA.
DR   EMBL; AF498975; AAM21122.1; -; mRNA.
DR   EMBL; BC014261; AAH14261.1; -; mRNA.
DR   CCDS; CCDS3458.1; -.
DR   PIR; I38367; I38367.
DR   RefSeq; NP_001265288.1; NM_001278359.1.
DR   RefSeq; NP_001265289.1; NM_001278360.1.
DR   RefSeq; NP_001265290.1; NM_001278361.1.
DR   RefSeq; NP_001265291.1; NM_001278362.1.
DR   RefSeq; NP_001265292.1; NM_001278363.1.
DR   RefSeq; NP_001265293.1; NM_001278364.1.
DR   RefSeq; NP_001265294.1; NM_001278365.1.
DR   RefSeq; NP_001265295.1; NM_001278366.1.
DR   RefSeq; NP_001265296.1; NM_001278367.1.
DR   RefSeq; NP_001265297.1; NM_001278368.1.
DR   RefSeq; NP_001265298.1; NM_001278369.1.
DR   RefSeq; NP_004301.1; NM_004310.4.
DR   RefSeq; XP_011511994.1; XM_011513692.1.
DR   RefSeq; XP_016863677.1; XM_017008188.1.
DR   RefSeq; XP_016863678.1; XM_017008189.1.
DR   AlphaFoldDB; Q15669; -.
DR   SMR; Q15669; -.
DR   BioGRID; 106892; 506.
DR   IntAct; Q15669; 20.
DR   MINT; Q15669; -.
DR   STRING; 9606.ENSP00000371219; -.
DR   GlyGen; Q15669; 1 site, 1 O-linked glycan (1 site).
DR   iPTMnet; Q15669; -.
DR   PhosphoSitePlus; Q15669; -.
DR   BioMuta; RHOH; -.
DR   DMDM; 2500200; -.
DR   jPOST; Q15669; -.
DR   MassIVE; Q15669; -.
DR   PaxDb; 9606-ENSP00000371219; -.
DR   PeptideAtlas; Q15669; -.
DR   ProteomicsDB; 60699; -.
DR   Antibodypedia; 23555; 284 antibodies from 29 providers.
DR   DNASU; 399; -.
DR   Ensembl; ENST00000381799.10; ENSP00000371219.4; ENSG00000168421.14.
DR   Ensembl; ENST00000503754.6; ENSP00000514769.1; ENSG00000168421.14.
DR   Ensembl; ENST00000503941.6; ENSP00000426439.2; ENSG00000168421.14.
DR   Ensembl; ENST00000503978.2; ENSP00000514775.1; ENSG00000168421.14.
DR   Ensembl; ENST00000505618.6; ENSP00000425010.1; ENSG00000168421.14.
DR   Ensembl; ENST00000507851.6; ENSP00000423384.2; ENSG00000168421.14.
DR   Ensembl; ENST00000508513.6; ENSP00000422241.2; ENSG00000168421.14.
DR   Ensembl; ENST00000511121.6; ENSP00000420866.2; ENSG00000168421.14.
DR   Ensembl; ENST00000511967.6; ENSP00000514770.1; ENSG00000168421.14.
DR   Ensembl; ENST00000513894.6; ENSP00000514771.1; ENSG00000168421.14.
DR   Ensembl; ENST00000515503.6; ENSP00000514774.1; ENSG00000168421.14.
DR   Ensembl; ENST00000515702.2; ENSP00000514772.1; ENSG00000168421.14.
DR   Ensembl; ENST00000515718.6; ENSP00000514773.1; ENSG00000168421.14.
DR   Ensembl; ENST00000614836.2; ENSP00000478248.1; ENSG00000168421.14.
DR   GeneID; 399; -.
DR   KEGG; hsa:399; -.
DR   MANE-Select; ENST00000381799.10; ENSP00000371219.4; NM_004310.5; NP_004301.1.
DR   AGR; HGNC:686; -.
DR   CTD; 399; -.
DR   DisGeNET; 399; -.
DR   GeneCards; RHOH; -.
DR   HGNC; HGNC:686; RHOH.
DR   HPA; ENSG00000168421; Group enriched (bone marrow, lymphoid tissue).
DR   MalaCards; RHOH; -.
DR   MIM; 602037; gene.
DR   MIM; 618307; phenotype.
DR   neXtProt; NX_Q15669; -.
DR   OpenTargets; ENSG00000168421; -.
DR   Orphanet; 324294; T-cell immunodeficiency with epidermodysplasia verruciformis.
DR   PharmGKB; PA24979; -.
DR   VEuPathDB; HostDB:ENSG00000168421; -.
DR   eggNOG; KOG0393; Eukaryota.
DR   GeneTree; ENSGT00940000160078; -.
DR   HOGENOM; CLU_041217_21_3_1; -.
DR   InParanoid; Q15669; -.
DR   OMA; HKWIAEV; -.
DR   OrthoDB; 20499at2759; -.
DR   PhylomeDB; Q15669; -.
DR   TreeFam; TF331219; -.
DR   BRENDA; 3.6.5.2; 2681.
DR   PathwayCommons; Q15669; -.
DR   Reactome; R-HSA-9013407; RHOH GTPase cycle.
DR   SignaLink; Q15669; -.
DR   SIGNOR; Q15669; -.
DR   BioGRID-ORCS; 399; 24 hits in 1150 CRISPR screens.
DR   ChiTaRS; RHOH; human.
DR   GeneWiki; RhoH; -.
DR   GenomeRNAi; 399; -.
DR   Pharos; Q15669; Tbio.
DR   PRO; PR:Q15669; -.
DR   Proteomes; UP000005640; Chromosome 4.
DR   RNAct; Q15669; Protein.
DR   Bgee; ENSG00000168421; Expressed in bone marrow cell and 114 other cell types or tissues.
DR   ExpressionAtlas; Q15669; baseline and differential.
DR   GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR   GO; GO:0001772; C:immunological synapse; IEA:Ensembl.
DR   GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR   GO; GO:0005525; F:GTP binding; IDA:UniProtKB.
DR   GO; GO:0003924; F:GTPase activity; IBA:GO_Central.
DR   GO; GO:0005095; F:GTPase inhibitor activity; NAS:UniProtKB.
DR   GO; GO:0019210; F:kinase inhibitor activity; IDA:UniProtKB.
DR   GO; GO:0019901; F:protein kinase binding; IBA:GO_Central.
DR   GO; GO:0031267; F:small GTPase binding; NAS:UniProtKB.
DR   GO; GO:0007015; P:actin filament organization; IBA:GO_Central.
DR   GO; GO:0045576; P:mast cell activation; IEA:Ensembl.
DR   GO; GO:0043124; P:negative regulation of canonical NF-kappaB signal transduction; IDA:UniProtKB.
DR   GO; GO:0045582; P:positive regulation of T cell differentiation; IMP:UniProtKB.
DR   GO; GO:0006355; P:regulation of DNA-templated transcription; NAS:UniProtKB.
DR   GO; GO:0007165; P:signal transduction; IBA:GO_Central.
DR   GO; GO:0007264; P:small GTPase mediated signal transduction; IEA:InterPro.
DR   GO; GO:0030217; P:T cell differentiation; NAS:UniProtKB.
DR   CDD; cd00157; Rho; 1.
DR   Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 1.
DR   InterPro; IPR027417; P-loop_NTPase.
DR   InterPro; IPR005225; Small_GTP-bd_dom.
DR   InterPro; IPR001806; Small_GTPase.
DR   InterPro; IPR003578; Small_GTPase_Rho.
DR   NCBIfam; TIGR00231; small_GTP; 1.
DR   PANTHER; PTHR24072; RHO FAMILY GTPASE; 1.
DR   PANTHER; PTHR24072:SF412; RHO-RELATED GTP-BINDING PROTEIN RHOH; 1.
DR   Pfam; PF00071; Ras; 1.
DR   PRINTS; PR00449; RASTRNSFRMNG.
DR   SMART; SM00175; RAB; 1.
DR   SMART; SM00173; RAS; 1.
DR   SMART; SM00174; RHO; 1.
DR   SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 1.
DR   PROSITE; PS51420; RHO; 1.
DR   Genevisible; Q15669; HS.
PE   1: Evidence at protein level;
KW   Cell membrane; Chromosomal rearrangement; Cytoplasm; Disease variant;
KW   GTP-binding; Lipoprotein; Membrane; Methylation; Nucleotide-binding;
KW   Phosphoprotein; Prenylation; Reference proteome.
FT   CHAIN           1..188
FT                   /note="Rho-related GTP-binding protein RhoH"
FT                   /id="PRO_0000198867"
FT   PROPEP          189..191
FT                   /note="Removed in mature form"
FT                   /evidence="ECO:0000250"
FT                   /id="PRO_0000281218"
FT   REGION          73..86
FT                   /note="Interaction with ZAP70"
FT                   /evidence="ECO:0000250"
FT   MOTIF           33..41
FT                   /note="Effector region"
FT                   /evidence="ECO:0000250"
FT   BINDING         11..18
FT                   /ligand="GTP"
FT                   /ligand_id="ChEBI:CHEBI:37565"
FT                   /evidence="ECO:0000250"
FT   BINDING         58..62
FT                   /ligand="GTP"
FT                   /ligand_id="ChEBI:CHEBI:37565"
FT                   /evidence="ECO:0000250"
FT   BINDING         116..119
FT                   /ligand="GTP"
FT                   /ligand_id="ChEBI:CHEBI:37565"
FT                   /evidence="ECO:0000250"
FT   MOD_RES         188
FT                   /note="Cysteine methyl ester"
FT                   /evidence="ECO:0000250"
FT   LIPID           188
FT                   /note="S-geranylgeranyl cysteine"
FT                   /evidence="ECO:0000250"
FT   VARIANT         38..191
FT                   /note="Missing (in EV4; loss-of-function variant resulting
FT                   in impaired T-cell differentiation; unable to rescue T-cell
FT                   lymphopenia in RHOH knockout mice; no protein detected in
FT                   patient cells; results in defective TCR signaling in
FT                   patient cells)"
FT                   /evidence="ECO:0000269|PubMed:22850876"
FT                   /id="VAR_081933"
SQ   SEQUENCE   191 AA;  21331 MW;  C5BF8929AD1E59D0 CRC64;
     MLSSIKCVLV GDSAVGKTSL LVRFTSETFP EAYKPTVYEN TGVDVFMDGI QISLGLWDTA
     GNDAFRSIRP LSYQQADVVL MCYSVANHNS FLNLKNKWIG EIRSNLPCTP VLVVATQTDQ
     REMGPHRASC VNAMEGKKLA QDVRAKGYLE CSALSNRGVQ QVFECAVRTA VNQARRRNRR
     RLFSINECKI F
//