UniProt functional annotation for P08754



	UniProt functional annotation for P08754

UniProt code: P08754.

Organism: Homo sapiens (Human).

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

Function: Heterotrimeric guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs) in numerous signaling cascades. The alpha chain contains the guanine nucleotide binding site and alternates between an active, GTP-bound state and an inactive, GDP-bound state. Signaling by an activated GPCR promotes GDP release and GTP binding. The alpha subunit has a low GTPase activity that converts bound GTP to GDP, thereby terminating the signal. Both GDP release and GTP hydrolysis are modulated by numerous regulatory proteins (PubMed:8774883, PubMed:18434541, PubMed:19478087). Signaling is mediated via effector proteins, such as adenylate cyclase. Inhibits adenylate cyclase activity, leading to decreased intracellular cAMP levels (PubMed:19478087). Stimulates the activity of receptor-regulated K(+) channels (PubMed:2535845). The active GTP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division (PubMed:17635935). {ECO:0000269|PubMed:17635935, ECO:0000269|PubMed:18434541, ECO:0000269|PubMed:2535845, ECO:0000269|PubMed:8774883}.

Subunit: Heterotrimeric G proteins are composed of 3 units; alpha, beta and gamma. The alpha subunit contains the guanine nucleotide binding site. GTP binding causes dissociation of the heterotrimer, liberating the individual subunits so that they can interact with downstream effector proteins. Forms a complex with CCDC88A/GIV and EGFR which leads to enhanced EGFR signaling and triggering of cell migration; ligand stimulation is required for recruitment of GNAI3 to the complex (PubMed:20462955). Interacts (inactive GDP-bound form) with CCDC88A/GIV (via GBA motif); the interaction leads to activation of GNAI3 (PubMed:19211784, PubMed:20462955). Interacts (inactive GDP-bound form) with CCDC88C/DAPLE (via GBA motif); the interaction leads to activation of GNAI3 (PubMed:26126266). Interacts (inactive GDP-bound form) with NUCB1 (via GBA motif) and NUCB2 (via GBA motif); the interaction leads to activation of GNAI3 (By similarity). Interacts (inactive GDP-bound form) with PLCD4 (via GBA motif); the interaction leads to activation of GNAI3 (PubMed:30194280). Interacts with INSR; the interaction is probably mediated by CCDC88A/GIV (PubMed:25187647). Interacts with GPSM1 (By similarity). Interacts (GDP-bound form) with GPSM2 (via GoLoco domains) (PubMed:22952234). Does not interact with RGS2 (PubMed:19478087). Interacts with RGS8 and RGS10; this strongly enhances the intrinsic GTPase activity (PubMed:8774883, PubMed:18434541). Interacts with RGS16; this strongly enhances the intrinsic GTPase activity (PubMed:19478087). Interacts with RGS12 (By similarity). Interacts (via active GTP- or inactive GDP-bound form) with RGS14 (By similarity). {ECO:0000250|UniProtKB:P08753, ECO:0000250|UniProtKB:Q9DC51, ECO:0000269|PubMed:18434541, ECO:0000269|PubMed:19211784, ECO:0000269|PubMed:19478087, ECO:0000269|PubMed:20462955, ECO:0000269|PubMed:22952234, ECO:0000269|PubMed:25187647, ECO:0000269|PubMed:26126266, ECO:0000269|PubMed:30194280, ECO:0000305}.

Subcellular location: Cytoplasm {ECO:0000269|PubMed:17635935}. Cell membrane {ECO:0000269|PubMed:17635935, ECO:0000269|PubMed:27864364}; Lipid-anchor {ECO:0000305}. Cytoplasm, cytoskeleton, microtubule organizing center, centrosome {ECO:0000269|PubMed:17635935}. Note=Localizes in the centrosomes of interphase and mitotic cells. Detected at the cleavage furrow and/or the midbody. {ECO:0000269|PubMed:17635935}.

Ptm: (Microbial infection) Deamidated at Gln-204 by Photorhabdus asymbiotica toxin PAU_02230, blocking GTP hydrolysis of heterotrimeric GNAQ or GNA11 and G-alphai (GNAI1, GNAI2 or GNAI3) proteins, thereby activating RhoA. {ECO:0000269|PubMed:24141704}.

Disease: Auriculocondylar syndrome 1 (ARCND1) [MIM:602483]: An autosomal dominant craniofacial malformation syndrome characterized by variable mandibular anomalies, including mild to severe micrognathia, temporomandibular joint ankylosis, cleft palate, and a characteristic ear malformation that consists of separation of the lobule from the external ear, giving the appearance of a question mark (question-mark ear). Other frequently described features include prominent cheeks, cupped and posteriorly rotated ears, preauricular tags, and microstomia. {ECO:0000269|PubMed:22560091}. Note=The disease is caused by variants affecting the gene represented in this entry.

Similarity: Belongs to the G-alpha family. G(i/o/t/z) subfamily. {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:		Heterotrimeric guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs) in numerous signaling cascades. The alpha chain contains the guanine nucleotide binding site and alternates between an active, GTP-bound state and an inactive, GDP-bound state. Signaling by an activated GPCR promotes GDP release and GTP binding. The alpha subunit has a low GTPase activity that converts bound GTP to GDP, thereby terminating the signal. Both GDP release and GTP hydrolysis are modulated by numerous regulatory proteins (PubMed:8774883, PubMed:18434541, PubMed:19478087). Signaling is mediated via effector proteins, such as adenylate cyclase. Inhibits adenylate cyclase activity, leading to decreased intracellular cAMP levels (PubMed:19478087). Stimulates the activity of receptor-regulated K(+) channels (PubMed:2535845). The active GTP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division (PubMed:17635935). {ECO:0000269\|PubMed:17635935, ECO:0000269\|PubMed:18434541, ECO:0000269\|PubMed:2535845, ECO:0000269\|PubMed:8774883}.


Subunit:		Heterotrimeric G proteins are composed of 3 units; alpha, beta and gamma. The alpha subunit contains the guanine nucleotide binding site. GTP binding causes dissociation of the heterotrimer, liberating the individual subunits so that they can interact with downstream effector proteins. Forms a complex with CCDC88A/GIV and EGFR which leads to enhanced EGFR signaling and triggering of cell migration; ligand stimulation is required for recruitment of GNAI3 to the complex (PubMed:20462955). Interacts (inactive GDP-bound form) with CCDC88A/GIV (via GBA motif); the interaction leads to activation of GNAI3 (PubMed:19211784, PubMed:20462955). Interacts (inactive GDP-bound form) with CCDC88C/DAPLE (via GBA motif); the interaction leads to activation of GNAI3 (PubMed:26126266). Interacts (inactive GDP-bound form) with NUCB1 (via GBA motif) and NUCB2 (via GBA motif); the interaction leads to activation of GNAI3 (By similarity). Interacts (inactive GDP-bound form) with PLCD4 (via GBA motif); the interaction leads to activation of GNAI3 (PubMed:30194280). Interacts with INSR; the interaction is probably mediated by CCDC88A/GIV (PubMed:25187647). Interacts with GPSM1 (By similarity). Interacts (GDP-bound form) with GPSM2 (via GoLoco domains) (PubMed:22952234). Does not interact with RGS2 (PubMed:19478087). Interacts with RGS8 and RGS10; this strongly enhances the intrinsic GTPase activity (PubMed:8774883, PubMed:18434541). Interacts with RGS16; this strongly enhances the intrinsic GTPase activity (PubMed:19478087). Interacts with RGS12 (By similarity). Interacts (via active GTP- or inactive GDP-bound form) with RGS14 (By similarity). {ECO:0000250\|UniProtKB:P08753, ECO:0000250\|UniProtKB:Q9DC51, ECO:0000269\|PubMed:18434541, ECO:0000269\|PubMed:19211784, ECO:0000269\|PubMed:19478087, ECO:0000269\|PubMed:20462955, ECO:0000269\|PubMed:22952234, ECO:0000269\|PubMed:25187647, ECO:0000269\|PubMed:26126266, ECO:0000269\|PubMed:30194280, ECO:0000305}.
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:17635935}. Cell membrane {ECO:0000269\|PubMed:17635935, ECO:0000269\|PubMed:27864364}; Lipid-anchor {ECO:0000305}. Cytoplasm, cytoskeleton, microtubule organizing center, centrosome {ECO:0000269\|PubMed:17635935}. Note=Localizes in the centrosomes of interphase and mitotic cells. Detected at the cleavage furrow and/or the midbody. {ECO:0000269\|PubMed:17635935}.
Ptm:		(Microbial infection) Deamidated at Gln-204 by Photorhabdus asymbiotica toxin PAU_02230, blocking GTP hydrolysis of heterotrimeric GNAQ or GNA11 and G-alphai (GNAI1, GNAI2 or GNAI3) proteins, thereby activating RhoA. {ECO:0000269\|PubMed:24141704}.
Disease:		Auriculocondylar syndrome 1 (ARCND1) [MIM:602483]: An autosomal dominant craniofacial malformation syndrome characterized by variable mandibular anomalies, including mild to severe micrognathia, temporomandibular joint ankylosis, cleft palate, and a characteristic ear malformation that consists of separation of the lobule from the external ear, giving the appearance of a question mark (question-mark ear). Other frequently described features include prominent cheeks, cupped and posteriorly rotated ears, preauricular tags, and microstomia. {ECO:0000269\|PubMed:22560091}. Note=The disease is caused by variants affecting the gene represented in this entry.
Similarity:		Belongs to the G-alpha family. G(i/o/t/z) subfamily. {ECO:0000305}.