UniProt functional annotation for O95267



	UniProt functional annotation for O95267

UniProt code: O95267.

Organism: Homo sapiens (Human).

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

Function: Functions as a calcium- and diacylglycerol (DAG)-regulated nucleotide exchange factor specifically activating Ras through the exchange of bound GDP for GTP (PubMed:15899849, PubMed:23908768, PubMed:27776107, PubMed:29155103). Activates the Erk/MAP kinase cascade (PubMed:15899849). Regulates T-cell/B-cell development, homeostasis and differentiation by coupling T-lymphocyte/B-lymphocyte antigen receptors to Ras (PubMed:10807788, PubMed:12839994, PubMed:27776107, PubMed:29155103). Regulates NK cell cytotoxicity and ITAM-dependent cytokine production by activation of Ras-mediated ERK and JNK pathways (PubMed:19933860). Functions in mast cell degranulation and cytokine secretion, regulating FcERI-evoked allergic responses. May also function in differentiation of other cell types (PubMed:12845332). {ECO:0000250|UniProtKB:Q9Z1S3, ECO:0000269|PubMed:10807788, ECO:0000269|PubMed:12782630, ECO:0000269|PubMed:12839994, ECO:0000269|PubMed:12845332, ECO:0000269|PubMed:15060167, ECO:0000269|PubMed:15184873, ECO:0000269|PubMed:15899849, ECO:0000269|PubMed:19933860, ECO:0000269|PubMed:23908768, ECO:0000269|PubMed:27776107, ECO:0000269|PubMed:29155103}.

Activity regulation: Autoinhibited. Activated by diacylglycerol and calcium binding, which induces a conformational change releasing the autoinhibitory state (PubMed:23908768). Regulated by DGKA (PubMed:11919165). Regulated by DGKZ (PubMed:11257115). Regulated by PLC gamma and F-actin polymerization (PubMed:12839994). {ECO:0000269|PubMed:11257115, ECO:0000269|PubMed:11919165, ECO:0000269|PubMed:12839994, ECO:0000269|PubMed:23908768}.

Subunit: Homodimer (PubMed:23908768). Forms a signaling complex with DGKZ and HRAS (PubMed:11257115). Interacts with F-actin (PubMed:12839994). Interacts with SKAP1 (PubMed:17658605). {ECO:0000269|PubMed:11257115, ECO:0000269|PubMed:12839994, ECO:0000269|PubMed:17658605, ECO:0000269|PubMed:23908768}.

Subcellular location: Cytoplasm, cytosol. Cell membrane; Peripheral membrane protein. Golgi apparatus membrane; Peripheral membrane protein. Endoplasmic reticulum membrane; Peripheral membrane protein. Note=Found both in the cytosol and associated with membranes. Relocalization to the cell membrane upon activation is F-actin- dependent. Translocates to the Golgi in response to phorbol ester or nerve growth factor. Localizes to somata and dendrites but not to axons of hippocampal pyramidal cells (By similarity). {ECO:0000250}.

Tissue specificity: Expressed in brain with higher expression in cerebellum, cerebral cortex and amygdala. Expressed in the hematopoietic system. Expressed in T-cells (at protein level). Expressed in NK cells (at protein level) (PubMed:19933860). {ECO:0000269|PubMed:10807788, ECO:0000269|PubMed:17878389, ECO:0000269|PubMed:19933860, ECO:0000269|PubMed:9789079}.

Developmental stage: Expressed in fetal brain and kidney. {ECO:0000269|PubMed:9789079}.

Domain: The phorbol-ester/DAG-type zinc finger is the principal mediator of the targeting to membranes and is required for functional activation through DAG-binding.

Domain: Two EF-hand domains are present. However, only EF-hand 1 (and not EF-hand 2) binds calcium. {ECO:0000269|PubMed:23908768}.

Disease: Systemic lupus erythematosus (SLE) [MIM:152700]: A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. {ECO:0000269|PubMed:17878389}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry. Aberrantly spliced isoforms and/or diminished levels of RASGRP1 are found in a cohort of SLE patients raising the possibility that dysregulation of this signaling protein contributes to the development of autoimmunity in a subset of SLE patients.

Disease: Immunodeficiency 64 (IMD64) [MIM:618534]: An autosomal recessive primary immunodeficiency characterized by recurrent bacterial, viral and fungal infections, variably decreased numbers of T cells, deficiencies of B and NK cells, and increased susceptibility to Epstein-Barr virus (EBV) infection. Patients may develop lymphoproliferation or EBV-associated lymphoma. Some patients may develop features of autoimmunity. {ECO:0000269|PubMed:27776107, ECO:0000269|PubMed:28822832, ECO:0000269|PubMed:29155103}. Note=The disease is caused by variants affecting the gene represented in this entry.

Similarity: Belongs to the RASGRP family. {ECO:0000305}.

Sequence caution: Sequence=AAH67298.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={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:		Functions as a calcium- and diacylglycerol (DAG)-regulated nucleotide exchange factor specifically activating Ras through the exchange of bound GDP for GTP (PubMed:15899849, PubMed:23908768, PubMed:27776107, PubMed:29155103). Activates the Erk/MAP kinase cascade (PubMed:15899849). Regulates T-cell/B-cell development, homeostasis and differentiation by coupling T-lymphocyte/B-lymphocyte antigen receptors to Ras (PubMed:10807788, PubMed:12839994, PubMed:27776107, PubMed:29155103). Regulates NK cell cytotoxicity and ITAM-dependent cytokine production by activation of Ras-mediated ERK and JNK pathways (PubMed:19933860). Functions in mast cell degranulation and cytokine secretion, regulating FcERI-evoked allergic responses. May also function in differentiation of other cell types (PubMed:12845332). {ECO:0000250\|UniProtKB:Q9Z1S3, ECO:0000269\|PubMed:10807788, ECO:0000269\|PubMed:12782630, ECO:0000269\|PubMed:12839994, ECO:0000269\|PubMed:12845332, ECO:0000269\|PubMed:15060167, ECO:0000269\|PubMed:15184873, ECO:0000269\|PubMed:15899849, ECO:0000269\|PubMed:19933860, ECO:0000269\|PubMed:23908768, ECO:0000269\|PubMed:27776107, ECO:0000269\|PubMed:29155103}.


Activity regulation:		Autoinhibited. Activated by diacylglycerol and calcium binding, which induces a conformational change releasing the autoinhibitory state (PubMed:23908768). Regulated by DGKA (PubMed:11919165). Regulated by DGKZ (PubMed:11257115). Regulated by PLC gamma and F-actin polymerization (PubMed:12839994). {ECO:0000269\|PubMed:11257115, ECO:0000269\|PubMed:11919165, ECO:0000269\|PubMed:12839994, ECO:0000269\|PubMed:23908768}.
Subunit:		Homodimer (PubMed:23908768). Forms a signaling complex with DGKZ and HRAS (PubMed:11257115). Interacts with F-actin (PubMed:12839994). Interacts with SKAP1 (PubMed:17658605). {ECO:0000269\|PubMed:11257115, ECO:0000269\|PubMed:12839994, ECO:0000269\|PubMed:17658605, ECO:0000269\|PubMed:23908768}.
Subcellular location:		Cytoplasm, cytosol. Cell membrane; Peripheral membrane protein. Golgi apparatus membrane; Peripheral membrane protein. Endoplasmic reticulum membrane; Peripheral membrane protein. Note=Found both in the cytosol and associated with membranes. Relocalization to the cell membrane upon activation is F-actin- dependent. Translocates to the Golgi in response to phorbol ester or nerve growth factor. Localizes to somata and dendrites but not to axons of hippocampal pyramidal cells (By similarity). {ECO:0000250}.
Tissue specificity:		Expressed in brain with higher expression in cerebellum, cerebral cortex and amygdala. Expressed in the hematopoietic system. Expressed in T-cells (at protein level). Expressed in NK cells (at protein level) (PubMed:19933860). {ECO:0000269\|PubMed:10807788, ECO:0000269\|PubMed:17878389, ECO:0000269\|PubMed:19933860, ECO:0000269\|PubMed:9789079}.
Developmental stage:		Expressed in fetal brain and kidney. {ECO:0000269\|PubMed:9789079}.
Domain:		The phorbol-ester/DAG-type zinc finger is the principal mediator of the targeting to membranes and is required for functional activation through DAG-binding.
Domain:		Two EF-hand domains are present. However, only EF-hand 1 (and not EF-hand 2) binds calcium. {ECO:0000269\|PubMed:23908768}.
Disease:		Systemic lupus erythematosus (SLE) [MIM:152700]: A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. {ECO:0000269\|PubMed:17878389}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry. Aberrantly spliced isoforms and/or diminished levels of RASGRP1 are found in a cohort of SLE patients raising the possibility that dysregulation of this signaling protein contributes to the development of autoimmunity in a subset of SLE patients.
Disease:		Immunodeficiency 64 (IMD64) [MIM:618534]: An autosomal recessive primary immunodeficiency characterized by recurrent bacterial, viral and fungal infections, variably decreased numbers of T cells, deficiencies of B and NK cells, and increased susceptibility to Epstein-Barr virus (EBV) infection. Patients may develop lymphoproliferation or EBV-associated lymphoma. Some patients may develop features of autoimmunity. {ECO:0000269\|PubMed:27776107, ECO:0000269\|PubMed:28822832, ECO:0000269\|PubMed:29155103}. Note=The disease is caused by variants affecting the gene represented in this entry.
Similarity:		Belongs to the RASGRP family. {ECO:0000305}.
Sequence caution:		Sequence=AAH67298.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305};