UniProt functional annotation for P61586



	UniProt functional annotation for P61586

UniProt code: P61586.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Small GTPase which cycles between an active GTP-bound and an inactive GDP-bound state. Mainly associated with cytoskeleton organization, in active state binds to a variety of effector proteins to regulate cellular responses such as cytoskeletal dynamics, cell migration and cell cycle. Regulates a signal transduction pathway linking plasma membrane receptors to the assembly of focal adhesions and actin stress fibers (PubMed:8910519, PubMed:9121475, PubMed:31570889). Involved in a microtubule-dependent signal that is required for the myosin contractile ring formation during cell cycle cytokinesis (PubMed:16236794, PubMed:12900402). Plays an essential role in cleavage furrow formation. Required for the apical junction formation of keratinocyte cell-cell adhesion (PubMed:20974804, PubMed:23940119). Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly (PubMed:19934221). The MEMO1-RHOA-DIAPH1 signaling pathway plays an important role in ERBB2- dependent stabilization of microtubules at the cell cortex. It controls the localization of APC and CLASP2 to the cell membrane, via the regulation of GSK3B activity. In turn, membrane-bound APC allows the localization of the MACF1 to the cell membrane, which is required for microtubule capture and stabilization (PubMed:20937854). Regulates KCNA2 potassium channel activity by reducing its location at the cell surface in response to CHRM1 activation; promotes KCNA2 endocytosis (PubMed:9635436, PubMed:19403695). Acts as an allosteric activator of guanine nucleotide exchange factor ECT2 by binding in its activated GTP-bound form to the PH domain of ECT2 which stimulates the release of PH inhibition and promotes the binding of substrate RHOA to the ECT2 catalytic center (PubMed:31888991). May be an activator of PLCE1 (PubMed:16103226). In neurons, involved in the inhibiton of the initial spine growth. Upon activation by CaMKII, modulates dendritic spine structural plasticity by relaying CaMKII transient activation to synapse-specific, long-term signaling (By similarity). Acts as a regulator of platelet alpha-granule release during activation and aggregation of platelets (By similarity). {ECO:0000250|UniProtKB:P61589, ECO:0000250|UniProtKB:Q9QUI0, ECO:0000269|PubMed:12900402, ECO:0000269|PubMed:16103226, ECO:0000269|PubMed:16236794, ECO:0000269|PubMed:19403695, ECO:0000269|PubMed:19934221, ECO:0000269|PubMed:20937854, ECO:0000269|PubMed:20974804, ECO:0000269|PubMed:23940119, ECO:0000269|PubMed:31570889, ECO:0000269|PubMed:31888991, ECO:0000269|PubMed:8910519, ECO:0000269|PubMed:9121475, ECO:0000269|PubMed:9635436}.

Function: (Microbial infection) Serves as a target for the yopT cysteine peptidase from Yersinia pestis, vector of the plague. {ECO:0000269|PubMed:12062101, ECO:0000269|PubMed:12538863}.

Catalytic activity: Reaction=GTP + H2O = GDP + H(+) + phosphate; Xref=Rhea:RHEA:19669, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:37565, ChEBI:CHEBI:43474, ChEBI:CHEBI:58189; EC=3.6.5.2; Evidence={ECO:0000269|PubMed:21565175, ECO:0000269|PubMed:23940119}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19670; Evidence={ECO:0000305|PubMed:21565175, ECO:0000305|PubMed:23940119};

Cofactor: Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000269|PubMed:12777804};

Activity regulation: Regulated by guanine nucleotide exchange factors (GEFs) which promote the exchange of bound GDP for free GTP, GTPase activating proteins (GAPs) which increase the GTP hydrolysis activity and GDP dissociation inhibitors which inhibit the dissociation of the nucleotide from the GTPase. Activated by GEFs such as ARHGEF2, ARHGEF3, ARHGEF28 and BCR (PubMed:23940119, PubMed:12221096). Inhibited by GAPs such as ARHGAP30 (PubMed:21565175). Inhibited by GDP dissociation inhibitors such as ARHGDIA (PubMed:20400958). {ECO:0000269|PubMed:12221096, ECO:0000269|PubMed:20400958, ECO:0000269|PubMed:21565175, ECO:0000269|PubMed:23940119}.

Subunit: Interacts with ARHGEF28 (By similarity). Interacts (via GTP- bound form) with RIPOR1 (via N-terminus); this interaction links RHOA to STK24 and STK26 kinases (PubMed:27807006). Interacts with RIPOR2 (via active GTP- or inactive GDP-bound forms) isoform 1 and isoform 2; these interactions are direct, block the loading of GTP to RHOA and decrease upon chemokine CCL19 stimulation in primary T lymphocytes (PubMed:25588844). Binds PRKCL1, ROCK1 and ROCK2 (PubMed:10388627, PubMed:8617235, PubMed:8641286). Interacts with ARHGEF2, ARHGEF3, NET1 and RTKN (PubMed:10940294, PubMed:12221096, PubMed:9857026). Interacts with PLCE1 and AKAP13 (PubMed:11696353, PubMed:12900402). Interacts with DIAPH1 (PubMed:23325789). Interacts (in the constitutively activated, GTP-bound form) with DGKQ (PubMed:10066731). Interacts with RACK1; enhances RHOA activation (PubMed:20499158). Interacts with PKP4; the interaction is detected at the midbody (PubMed:17115030). Interacts (GTP-bound form preferentially) with PKN2; the interaction stimulates autophosphorylation and phosphorylation of PKN2 (PubMed:20974804, PubMed:9121475). Interacts with ARHGDIA; this interaction inactivates and stabilizes RHOA (PubMed:20400958). Interacts with ARHGDIB. Interacts (GTP-bound form) with KCNA2 (via cytoplasmic N-terminal domain) (PubMed:9635436). Interacts (GTP-bound form) with ECT2; the interaction results in allosteric activation of ECT2 (PubMed:31888991). {ECO:0000250|UniProtKB:Q9QUI0, ECO:0000269|PubMed:10066731, ECO:0000269|PubMed:10388627, ECO:0000269|PubMed:10940294, ECO:0000269|PubMed:11696353, ECO:0000269|PubMed:12221096, ECO:0000269|PubMed:12900402, ECO:0000269|PubMed:17115030, ECO:0000269|PubMed:20400958, ECO:0000269|PubMed:20499158, ECO:0000269|PubMed:20974804, ECO:0000269|PubMed:25588844, ECO:0000269|PubMed:27807006, ECO:0000269|PubMed:31888991, ECO:0000269|PubMed:8617235, ECO:0000269|PubMed:8641286, ECO:0000269|PubMed:9121475, ECO:0000269|PubMed:9857026, ECO:0000305|PubMed:9635436}.

Subunit: (Microbial infection) Interacts with yopT from Yersinia pestis. {ECO:0000269|PubMed:12062101, ECO:0000269|PubMed:12538863}.

Subunit: (Microbial infection) Interacts with human respiratory syncytial virus (HRSV) protein F; this interaction facilitates virus- induced syncytium formation. {ECO:0000269|PubMed:10438814}.

Subcellular location: Cell membrane; Lipid-anchor; Cytoplasmic side. Cytoplasm, cytoskeleton. Cleavage furrow. Cytoplasm, cell cortex {ECO:0000269|PubMed:9635436}. Midbody. Cell projection, lamellipodium {ECO:0000250|UniProtKB:Q9QUI0}. Cell projection, dendrite {ECO:0000250|UniProtKB:Q9QUI0}. Note=Localized to cell-cell contacts in calcium-treated keratinocytes (By similarity). Translocates to the equatorial region before furrow formation in a ECT2-dependent manner. Localizes to the equatorial cell cortex (at the site of the presumptive furrow) in early anaphase in an activated form and in a myosin- and actin-independent manner. {ECO:0000250|UniProtKB:Q9QUI0}.

Domain: The basic-rich region is essential for yopT recognition and cleavage.

Ptm: (Microbial infection) Substrate for botulinum ADP- ribosyltransferase. {ECO:0000269|PubMed:1328215}.

Ptm: (Microbial infection) Cleaved by yopT protease when the cell is infected by some Yersinia pathogens. This removes the lipid attachment, and leads to its displacement from plasma membrane and to subsequent cytoskeleton cleavage. {ECO:0000269|PubMed:12062101, ECO:0000269|PubMed:12538863}.

Ptm: (Microbial infection) AMPylation at Tyr-34 and Thr-37 are mediated by bacterial enzymes in case of infection by H.somnus and V.parahaemolyticus, respectively. AMPylation occurs in the effector region and leads to inactivation of the GTPase activity by preventing the interaction with downstream effectors, thereby inhibiting actin assembly in infected cells. It is unclear whether some human enzyme mediates AMPylation; FICD has such ability in vitro but additional experiments remain to be done to confirm results in vivo. {ECO:0000269|PubMed:19039103, ECO:0000269|PubMed:19362538}.

Ptm: (Microbial infection) Glycosylated at Tyr-34 by Photorhabdus asymbiotica toxin PAU_02230. Mono-O-GlcNAcylation by PAU_02230 inhibits downstream signaling by an impaired interaction with diverse regulator and effector proteins of Rho and leads to actin disassembly. {ECO:0000269|PubMed:24141704}.

Ptm: (Microbial infection) Glucosylated at Thr-37 by C.difficile toxins TcdA and TcdB in the colonic epithelium (PubMed:7777059, PubMed:7775453, PubMed:24905543). Monoglucosylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption and cell death, resulting in the loss of colonic epithelial barrier function (PubMed:7777059, PubMed:7775453). {ECO:0000269|PubMed:24905543, ECO:0000269|PubMed:7775453, ECO:0000269|PubMed:7777059}.

Ptm: (Microbial infection) Glycosylated (O-GlcNAcylated) at Thr-37 by C.novyi toxin TcdA (PubMed:8810274). O-GlcNAcylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption (PubMed:8810274). {ECO:0000269|PubMed:8810274}.

Ptm: Phosphorylation by PRKG1 at Ser-188 inactivates RHOA signaling (PubMed:11162591). Phosphorylation by SLK at Ser-188 in response to AGTR2 activation (By similarity). {ECO:0000250|UniProtKB:P61589, ECO:0000269|PubMed:11162591}.

Ptm: Ubiquitinated by the BCR(KCTD13) and BCR(TNFAIP1) E3 ubiquitin ligase complexes, leading to its degradation by the proteasome, thereby regulating the actin cytoskeleton and synaptic transmission in neurons. {ECO:0000269|PubMed:19782033}.

Ptm: Serotonylation of Gln-63 by TGM2 during activation and aggregation of platelets leads to constitutive activation of GTPase activity. {ECO:0000250|UniProtKB:Q9QUI0}.

Disease: Ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies (EDFAOB) [MIM:618727]: A neuroectodermal syndrome characterized by linear hypopigmentation, alopecia, apparently asymptomatic leukoencephalopathy, and facial, ocular, dental and acral anomalies. Patients show no intellectual or neurologic impairment. {ECO:0000269|PubMed:31570889}. Note=The disease is caused by variants affecting the gene represented in this entry.

Similarity: Belongs to the small GTPase superfamily. Rho family. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Small GTPase which cycles between an active GTP-bound and an inactive GDP-bound state. Mainly associated with cytoskeleton organization, in active state binds to a variety of effector proteins to regulate cellular responses such as cytoskeletal dynamics, cell migration and cell cycle. Regulates a signal transduction pathway linking plasma membrane receptors to the assembly of focal adhesions and actin stress fibers (PubMed:8910519, PubMed:9121475, PubMed:31570889). Involved in a microtubule-dependent signal that is required for the myosin contractile ring formation during cell cycle cytokinesis (PubMed:16236794, PubMed:12900402). Plays an essential role in cleavage furrow formation. Required for the apical junction formation of keratinocyte cell-cell adhesion (PubMed:20974804, PubMed:23940119). Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly (PubMed:19934221). The MEMO1-RHOA-DIAPH1 signaling pathway plays an important role in ERBB2- dependent stabilization of microtubules at the cell cortex. It controls the localization of APC and CLASP2 to the cell membrane, via the regulation of GSK3B activity. In turn, membrane-bound APC allows the localization of the MACF1 to the cell membrane, which is required for microtubule capture and stabilization (PubMed:20937854). Regulates KCNA2 potassium channel activity by reducing its location at the cell surface in response to CHRM1 activation; promotes KCNA2 endocytosis (PubMed:9635436, PubMed:19403695). Acts as an allosteric activator of guanine nucleotide exchange factor ECT2 by binding in its activated GTP-bound form to the PH domain of ECT2 which stimulates the release of PH inhibition and promotes the binding of substrate RHOA to the ECT2 catalytic center (PubMed:31888991). May be an activator of PLCE1 (PubMed:16103226). In neurons, involved in the inhibiton of the initial spine growth. Upon activation by CaMKII, modulates dendritic spine structural plasticity by relaying CaMKII transient activation to synapse-specific, long-term signaling (By similarity). Acts as a regulator of platelet alpha-granule release during activation and aggregation of platelets (By similarity). {ECO:0000250\|UniProtKB:P61589, ECO:0000250\|UniProtKB:Q9QUI0, ECO:0000269\|PubMed:12900402, ECO:0000269\|PubMed:16103226, ECO:0000269\|PubMed:16236794, ECO:0000269\|PubMed:19403695, ECO:0000269\|PubMed:19934221, ECO:0000269\|PubMed:20937854, ECO:0000269\|PubMed:20974804, ECO:0000269\|PubMed:23940119, ECO:0000269\|PubMed:31570889, ECO:0000269\|PubMed:31888991, ECO:0000269\|PubMed:8910519, ECO:0000269\|PubMed:9121475, ECO:0000269\|PubMed:9635436}.



Function:		(Microbial infection) Serves as a target for the yopT cysteine peptidase from Yersinia pestis, vector of the plague. {ECO:0000269\|PubMed:12062101, ECO:0000269\|PubMed:12538863}.


Catalytic activity:		Reaction=GTP + H2O = GDP + H(+) + phosphate; Xref=Rhea:RHEA:19669, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:37565, ChEBI:CHEBI:43474, ChEBI:CHEBI:58189; EC=3.6.5.2; Evidence={ECO:0000269\|PubMed:21565175, ECO:0000269\|PubMed:23940119}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19670; Evidence={ECO:0000305\|PubMed:21565175, ECO:0000305\|PubMed:23940119};
Cofactor:		Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000269\|PubMed:12777804};
Activity regulation:		Regulated by guanine nucleotide exchange factors (GEFs) which promote the exchange of bound GDP for free GTP, GTPase activating proteins (GAPs) which increase the GTP hydrolysis activity and GDP dissociation inhibitors which inhibit the dissociation of the nucleotide from the GTPase. Activated by GEFs such as ARHGEF2, ARHGEF3, ARHGEF28 and BCR (PubMed:23940119, PubMed:12221096). Inhibited by GAPs such as ARHGAP30 (PubMed:21565175). Inhibited by GDP dissociation inhibitors such as ARHGDIA (PubMed:20400958). {ECO:0000269\|PubMed:12221096, ECO:0000269\|PubMed:20400958, ECO:0000269\|PubMed:21565175, ECO:0000269\|PubMed:23940119}.
Subunit:		Interacts with ARHGEF28 (By similarity). Interacts (via GTP- bound form) with RIPOR1 (via N-terminus); this interaction links RHOA to STK24 and STK26 kinases (PubMed:27807006). Interacts with RIPOR2 (via active GTP- or inactive GDP-bound forms) isoform 1 and isoform 2; these interactions are direct, block the loading of GTP to RHOA and decrease upon chemokine CCL19 stimulation in primary T lymphocytes (PubMed:25588844). Binds PRKCL1, ROCK1 and ROCK2 (PubMed:10388627, PubMed:8617235, PubMed:8641286). Interacts with ARHGEF2, ARHGEF3, NET1 and RTKN (PubMed:10940294, PubMed:12221096, PubMed:9857026). Interacts with PLCE1 and AKAP13 (PubMed:11696353, PubMed:12900402). Interacts with DIAPH1 (PubMed:23325789). Interacts (in the constitutively activated, GTP-bound form) with DGKQ (PubMed:10066731). Interacts with RACK1; enhances RHOA activation (PubMed:20499158). Interacts with PKP4; the interaction is detected at the midbody (PubMed:17115030). Interacts (GTP-bound form preferentially) with PKN2; the interaction stimulates autophosphorylation and phosphorylation of PKN2 (PubMed:20974804, PubMed:9121475). Interacts with ARHGDIA; this interaction inactivates and stabilizes RHOA (PubMed:20400958). Interacts with ARHGDIB. Interacts (GTP-bound form) with KCNA2 (via cytoplasmic N-terminal domain) (PubMed:9635436). Interacts (GTP-bound form) with ECT2; the interaction results in allosteric activation of ECT2 (PubMed:31888991). {ECO:0000250\|UniProtKB:Q9QUI0, ECO:0000269\|PubMed:10066731, ECO:0000269\|PubMed:10388627, ECO:0000269\|PubMed:10940294, ECO:0000269\|PubMed:11696353, ECO:0000269\|PubMed:12221096, ECO:0000269\|PubMed:12900402, ECO:0000269\|PubMed:17115030, ECO:0000269\|PubMed:20400958, ECO:0000269\|PubMed:20499158, ECO:0000269\|PubMed:20974804, ECO:0000269\|PubMed:25588844, ECO:0000269\|PubMed:27807006, ECO:0000269\|PubMed:31888991, ECO:0000269\|PubMed:8617235, ECO:0000269\|PubMed:8641286, ECO:0000269\|PubMed:9121475, ECO:0000269\|PubMed:9857026, ECO:0000305\|PubMed:9635436}.
Subunit:		(Microbial infection) Interacts with yopT from Yersinia pestis. {ECO:0000269\|PubMed:12062101, ECO:0000269\|PubMed:12538863}.
Subunit:		(Microbial infection) Interacts with human respiratory syncytial virus (HRSV) protein F; this interaction facilitates virus- induced syncytium formation. {ECO:0000269\|PubMed:10438814}.
Subcellular location:		Cell membrane; Lipid-anchor; Cytoplasmic side. Cytoplasm, cytoskeleton. Cleavage furrow. Cytoplasm, cell cortex {ECO:0000269\|PubMed:9635436}. Midbody. Cell projection, lamellipodium {ECO:0000250\|UniProtKB:Q9QUI0}. Cell projection, dendrite {ECO:0000250\|UniProtKB:Q9QUI0}. Note=Localized to cell-cell contacts in calcium-treated keratinocytes (By similarity). Translocates to the equatorial region before furrow formation in a ECT2-dependent manner. Localizes to the equatorial cell cortex (at the site of the presumptive furrow) in early anaphase in an activated form and in a myosin- and actin-independent manner. {ECO:0000250\|UniProtKB:Q9QUI0}.
Domain:		The basic-rich region is essential for yopT recognition and cleavage.
Ptm:		(Microbial infection) Substrate for botulinum ADP- ribosyltransferase. {ECO:0000269\|PubMed:1328215}.
Ptm:		(Microbial infection) Cleaved by yopT protease when the cell is infected by some Yersinia pathogens. This removes the lipid attachment, and leads to its displacement from plasma membrane and to subsequent cytoskeleton cleavage. {ECO:0000269\|PubMed:12062101, ECO:0000269\|PubMed:12538863}.
Ptm:		(Microbial infection) AMPylation at Tyr-34 and Thr-37 are mediated by bacterial enzymes in case of infection by H.somnus and V.parahaemolyticus, respectively. AMPylation occurs in the effector region and leads to inactivation of the GTPase activity by preventing the interaction with downstream effectors, thereby inhibiting actin assembly in infected cells. It is unclear whether some human enzyme mediates AMPylation; FICD has such ability in vitro but additional experiments remain to be done to confirm results in vivo. {ECO:0000269\|PubMed:19039103, ECO:0000269\|PubMed:19362538}.
Ptm:		(Microbial infection) Glycosylated at Tyr-34 by Photorhabdus asymbiotica toxin PAU_02230. Mono-O-GlcNAcylation by PAU_02230 inhibits downstream signaling by an impaired interaction with diverse regulator and effector proteins of Rho and leads to actin disassembly. {ECO:0000269\|PubMed:24141704}.
Ptm:		(Microbial infection) Glucosylated at Thr-37 by C.difficile toxins TcdA and TcdB in the colonic epithelium (PubMed:7777059, PubMed:7775453, PubMed:24905543). Monoglucosylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption and cell death, resulting in the loss of colonic epithelial barrier function (PubMed:7777059, PubMed:7775453). {ECO:0000269\|PubMed:24905543, ECO:0000269\|PubMed:7775453, ECO:0000269\|PubMed:7777059}.
Ptm:		(Microbial infection) Glycosylated (O-GlcNAcylated) at Thr-37 by C.novyi toxin TcdA (PubMed:8810274). O-GlcNAcylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption (PubMed:8810274). {ECO:0000269\|PubMed:8810274}.
Ptm:		Phosphorylation by PRKG1 at Ser-188 inactivates RHOA signaling (PubMed:11162591). Phosphorylation by SLK at Ser-188 in response to AGTR2 activation (By similarity). {ECO:0000250\|UniProtKB:P61589, ECO:0000269\|PubMed:11162591}.
Ptm:		Ubiquitinated by the BCR(KCTD13) and BCR(TNFAIP1) E3 ubiquitin ligase complexes, leading to its degradation by the proteasome, thereby regulating the actin cytoskeleton and synaptic transmission in neurons. {ECO:0000269\|PubMed:19782033}.
Ptm:		Serotonylation of Gln-63 by TGM2 during activation and aggregation of platelets leads to constitutive activation of GTPase activity. {ECO:0000250\|UniProtKB:Q9QUI0}.
Disease:		Ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies (EDFAOB) [MIM:618727]: A neuroectodermal syndrome characterized by linear hypopigmentation, alopecia, apparently asymptomatic leukoencephalopathy, and facial, ocular, dental and acral anomalies. Patients show no intellectual or neurologic impairment. {ECO:0000269\|PubMed:31570889}. Note=The disease is caused by variants affecting the gene represented in this entry.
Similarity:		Belongs to the small GTPase superfamily. Rho family. {ECO:0000305}.