Reviewed,
UniProtKB/Swiss-Prot O95267 (GRP1_HUMAN)
Last modified
November 25, 2008.
Version 58.
History...
Clusters with 100%,
90%,
50% identity |
Documents (3) |
Third-party data |
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Names and origin
| Protein names | Recommended name: RAS guanyl-releasing protein 1 Alternative name(s): Ras guanyl-releasing protein Calcium and DAG-regulated guanine nucleotide exchange factor II Short name=CalDAG-GEFII | ||||
| Gene names |
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| Organism | Homo sapiens (Human) | ||||
| Taxonomic identifier | 9606 [NCBI] | ||||
| Taxonomic lineage | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Protein attributes
| Sequence length | 797 AA. |
| Sequence status | Complete. |
| Sequence processing | The displayed sequence is not processed. |
| Protein existence | Evidence at protein level. |
General annotation (Comments)
| Function | Functions as a diacylglycerol (DAG)-regulated nucleotide exchange factor specifically activating Ras through the exchange of bound GDP for GTP. Activates the Erk/MAP kinase cascade. Couples T-lymphocytes and B-lymphocytes antigen receptors to the activation of Ras. Hence, regulates T-cells and B-cells development, homeostasis and differentiation. Functions also in FcERI-evoked degranulation and cytokine secretion by mast cells, regulating allergic responses. May also function in other cell types differentiation. |
| Enzyme regulation | Probably regulated by calcium By similarity. Regulated by PLC gamma, DGKA, DGKZ and by F-actin polymerization. |
| Subunit structure | Forms a signaling complex with DGKZ and HRAS. Interacts with F-actin. Interacts with SKAP1. |
| 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. |
| 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). |
| Developmental stage | Expressed in fetal brain and kidney. |
| 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. |
| Involvement in disease | Altered expression of the different RASGRP1 isoforms may be a cause of susceptibility to systemic lupus erythematosus (SLE) [MIM:152700]. SLE is a chronic, inflammatory and often febrile multisystemic disorder of connective tissue. It affects principally the skin, joints, kidneys and serosal membranes. SLE is thought to represent a failure of the regulatory mechanisms of the autoimmune system. |
| Sequence similarities | Belongs to the RASGRP family. Contains 2 EF-hand domains. Contains 1 N-terminal Ras-GEF domain. Contains 1 phorbol-ester/DAG-type zinc finger. Contains 1 Ras-GEF domain. |
| Sequence caution | The sequence AAH67298.1 differs from that shown. Reason: Miscellaneous discrepancy. Contaminating sequence. Potential poly-A sequence. |
Ontologies
Binary interactions
With | Entry | #Exp. | IntAct | Notes |
|---|---|---|---|---|
| PPM1B | O75688 | 1 | EBI-1054956,EBI-1047039 | |
| VHL | P40337 | 1 | EBI-1054956,EBI-301246 |
Alternative products
| This entry describes 5 isoforms produced by alternative splicing. [Align] [Select] Notes: Additional isoforms seem to exist. Several splicing events may be used independently in a modular way. | ||||||
| Isoform 1 (identifier: O95267-1) 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. | ||||||
| Isoform 2 (identifier: O95267-2) Also known as: A; The sequence of this isoform differs from the canonical sequence as follows: 442-476: Missing. | ||||||
| Isoform 3 (identifier: O95267-3) Also known as: B; The sequence of this isoform differs from the canonical sequence as follows: 442-476: Missing. 625-632: APEEGPFT → GNKYSESR 633-797: Missing. | ||||||
| Isoform 4 (identifier: O95267-4) Also known as: C; The sequence of this isoform differs from the canonical sequence as follows: 442-476: Missing. 513-516: REGL → SSGE 517-797: Missing. | ||||||
| Isoform 5 (identifier: O95267-5) Also known as: D; The sequence of this isoform differs from the canonical sequence as follows: 442-476: Missing. 574-581: DCGMNCHK → GNKYSESR 582-797: Missing. | ||||||
| Notes: No experimental confirmation available. |
Sequence annotation (Features)
| Feature key | Position(s) | Length | Description | Graphical view | Feature identifier | ||||
Molecule processing | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Chain | 1 – 797 | 797 | RAS guanyl-releasing protein 1 | PRO_0000316978 | |||||
Regions | |||||||||
| Domain | 53 – 176 | 124 | N-terminal Ras-GEF | ||||||
| Domain | 205 – 436 | 232 | Ras-GEF | ||||||
| Domain | 470 – 505 | 36 | EF-hand 1 | ||||||
| Domain | 497 – 532 | 36 | EF-hand 2 | ||||||
| Calcium binding | 483 – 494 | 12 | 1 Potential | ||||||
| Calcium binding | 510 – 521 | 12 | 2 Potential | ||||||
| Zinc finger | 541 – 591 | 51 | Phorbol-ester/DAG-type | ||||||
| Region | 57 – 110 | 54 | Ras exchanger motif region; required for transforming activity By similarity | ||||||
| Region | 686 – 694 | 9 | Suppress the PT region-mediated translocation to plasma membrane By similarity | ||||||
| Region | 718 – 797 | 80 | PT region; mediates the BCR-dependent translocation to plasma membrane By similarity | ||||||
| Coiled coil | 746 – 786 | 41 | Potential | ||||||
Amino acid modifications | |||||||||
| Modified residue | 184 | 1 | Phosphothreonine; by PKC | ||||||
Natural variations | |||||||||
| Alternative sequence | 442 – 476 | 35 | Missing in isoform 2, isoform 3, isoform 4 and isoform 5. | VSP_030836 | |||||
| Alternative sequence | 513 – 516 | 4 | REGL → SSGE in isoform 4. | VSP_030837 | |||||
| Alternative sequence | 517 – 797 | 281 | Missing in isoform 4. | VSP_030838 | |||||
| Alternative sequence | 574 – 581 | 8 | DCGMNCHK → GNKYSESR in isoform 5. | VSP_030839 | |||||
| Alternative sequence | 582 – 797 | 216 | Missing in isoform 5. | VSP_030840 | |||||
| Alternative sequence | 625 – 632 | 8 | APEEGPFT → GNKYSESR in isoform 3. | VSP_030841 | |||||
| Alternative sequence | 633 – 797 | 165 | Missing in isoform 3. | VSP_030842 | |||||
Experimental info | |||||||||
| Mutagenesis | 271 | 1 | R → E: Loss of function; prevents Ras activation | ||||||
| Mutagenesis | 549 | 1 | Y → F: Loss of localization to the endoplasmic reticulum and the Golgi apparatus | ||||||
| Sequence conflict | 374 | 1 | E → G in AAC79699 and AAF21898. Ref.1 | ||||||
Sequences
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References
| « Hide 'large scale' references | |
| [1] | "A Rap guanine nucleotide exchange factor enriched highly in the basal ganglia." Kawasaki H., Springett G.M., Toki S., Canales J.J., Harlan P., Blumenstiel J.P., Chen E.J., Bany I.A., Mochizuki N., Ashbacher A., Matsuda M., Housman D.E., Graybiel A.M. Proc. Natl. Acad. Sci. U.S.A. 95:13278-13283(1998) [PubMed: 9789079] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, DEVELOPMENTAL STAGE. Tissue: Frontal cortex. |
| [2] | "RasGRP, a Ras activator: mouse and human cDNA sequences and chromosomal positions." Bottorff D.A., Ebinu J.O., Stone J.C. Mamm. Genome 10:358-361(1999) [PubMed: 10087292] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: T-cell. |
| [3] | "Defective expression of ras guanyl nucleotide-releasing protein 1 in a subset of patients with systemic lupus erythematosus." Yasuda S., Stevens R.L., Terada T., Takeda M., Hashimoto T., Fukae J., Horita T., Kataoka H., Atsumi T., Koike T. J. Immunol. 179:4890-4900(2007) [PubMed: 17878389] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2; 3; 4 AND 5), INVOLVEMENT IN SYSTEMIC LUPUS ERYTHEMATOSUS, TISSUE SPECIFICITY. Tissue: Peripheral blood. |
| [4] | "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Testis. |
| [5] | Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S., Ohara O., Nagase T., Kikuno F.R. Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 233-797 (ISOFORM 2). Tissue: Brain. |
| [6] | "RasGRP links T-cell receptor signaling to Ras." Ebinu J.O., Stang S.L., Teixeira C., Bottorff D.A., Hooton J., Blumberg P.M., Barry M., Bleakley R.C., Ostergaard H.L., Stone J.C. Blood 95:3199-3203(2000) [PubMed: 10807788] [Abstract] Cited for: FUNCTION IN T-CELL RECEPTOR SIGNALING, TOPOLOGY, TISSUE SPECIFICITY. |
| [7] | "Diacylglycerol kinase zeta regulates Ras activation by a novel mechanism." Topham M.K., Prescott S.M. J. Cell Biol. 152:1135-1143(2001) [PubMed: 11257115] [Abstract] Cited for: IDENTIFICATION IN A COMPLEX WITH DGKZ AND HRAS, ENZYME REGULATION. |
| [8] | "Expression of a catalytically inactive form of diacylglycerol kinase alpha induces sustained signaling through RasGRP." Jones D.R., Sanjuan M.A., Stone J.C., Merida I. FASEB J. 16:595-597(2002) [PubMed: 11919165] [Abstract] Cited for: ENZYME REGULATION. |
| [9] | "Vav mediates Ras stimulation by direct activation of the GDP/GTP exchange factor Ras GRP1." Caloca M.J., Zugaza J.L., Matallanas D., Crespo P., Bustelo X.R. EMBO J. 22:3326-3336(2003) [PubMed: 12839994] [Abstract] Cited for: FUNCTION IN B-CELLS, SUBCELLULAR LOCATION, INTERACTION WITH F-ACTIN, ENZYME REGULATION. |
| [10] | "Exchange factors of the RasGRP family mediate Ras activation in the Golgi." Caloca M.J., Zugaza J.L., Bustelo X.R. J. Biol. Chem. 278:33465-33473(2003) [PubMed: 12782630] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, MUTAGENESIS OF TYR-549. |
| [11] | "Phospholipase Cgamma activates Ras on the Golgi apparatus by means of RasGRP1." Bivona T.G., Perez De Castro I., Ahearn I.M., Grana T.M., Chiu V.K., Lockyer P.J., Cullen P.J., Pellicer A., Cox A.D., Philips M.R. Nature 424:694-698(2003) [PubMed: 12845332] [Abstract] Cited for: FUNCTION, MUTAGENESIS OF ARG-271. |
| [12] | "Ras activation in Jurkat T cells following low-grade stimulation of the T-cell receptor is specific to N-Ras and occurs only on the Golgi apparatus." Perez de Castro I., Bivona T.G., Philips M.R., Pellicer A. Mol. Cell. Biol. 24:3485-3496(2004) [PubMed: 15060167] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION. |
| [13] | "Inverted signaling hierarchy between RAS and RAC in T-lymphocytes." Zugaza J.L., Caloca M.J., Bustelo X.R. Oncogene 23:5823-5833(2004) [PubMed: 15184873] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION. |
| [14] | "Phosphorylation of RasGRP3 on threonine 133 provides a mechanistic link between PKC and Ras signaling systems in B cells." Zheng Y., Liu H., Coughlin J.J., Zheng J., Li L., Stone J.C. Blood 105:3648-3654(2005) [PubMed: 15657177] [Abstract] Cited for: PHOSPHORYLATION AT THR-184 BY PKC. |
| [15] | "A diacylglycerol-protein kinase C-RasGRP1 pathway directs Ras activation upon antigen receptor stimulation of T cells." Roose J.P., Mollenauer M., Gupta V.A., Stone J.C., Weiss A. Mol. Cell. Biol. 25:4426-4441(2005) [PubMed: 15899849] [Abstract] Cited for: FUNCTION, PHOSPHORYLATION AT THR-184. |
| [16] | "SKAP55 modulates T cell antigen receptor-induced activation of the Ras-Erk-AP1 pathway by binding RasGRP1." Kosco K.A., Cerignoli F., Williams S., Abraham R.T., Mustelin T. Mol. Immunol. 45:510-522(2008) [PubMed: 17658605] [Abstract] Cited for: INTERACTION WITH SKAP1. |
| + | Additional computationally mapped references. |
Cross-references
Sequence databases | |
|---|---|
| AF081195 mRNA. Translation: AAC79699.1. AF081197 mRNA. Translation: AAF21898.1. AF106071 mRNA. Translation: AAC97349.1. AY634315 mRNA. Translation: AAT47482.2. AY858556 mRNA. Translation: AAW32406.2. AY954625 mRNA. Translation: AAX54699.4. AY966005 mRNA. Translation: AAX76907.1. BC067298 mRNA. Translation: AAH67298.1. Sequence problems. BC109296 mRNA. Translation: AAI09297.1. BC109297 mRNA. Translation: AAI09298.1. AB208848 mRNA. Translation: BAD92085.1. | |
| RefSeq | NP_005730.2. |
| UniGene | Hs.591127 |
3D structure databases | |
| HSSP | HSSP built from PDB template 1PTQ based on UniProtKB P28867. |
| ModBase | Search... |
Protein-protein interaction databases | |
| IntAct | O95267. |
PTM databases | |
| PhosphoSite | O95267. |
Genome annotation databases | |
| Ensembl | ENSG00000172575. Homo sapiens. [Contig view] |
| GeneID | 10125. |
Organism-specific databases | |
| HGNC | HGNC:9878. RASGRP1. |
| MIM | 152700. phenotype. 603962. gene. |
| PharmGKB | PA34240. |
| GenAtlas | Search... |
| GeneCards | Search... |
Phylogenomic databases | |
| HOGENOM | O95267. |
| HOVERGEN | O95267. |
Gene expression databases | |
| ArrayExpress | O95267. |
Family and domain databases | |
| InterPro | IPR002219. DAG_PE_bd. IPR011992. EF-Hand_type. IPR002048. EF_hand_Ca_bd. IPR008937. Ras_GEF. IPR000651. RasGef_N. IPR001895. RasGRF_CDC25. [Graphical view] |
| Gene3D | G3DSA:1.10.238.10. EF-Hand_type. 1 hit. G3DSA:1.10.840.10. RasGRF_CDC25. 1 hit. |
| PANTHER | PTHR23113. Ras_GEF. 1 hit. |
| Pfam | PF00130. C1_1. 1 hit. PF00036. efhand. 2 hits. PF00617. RasGEF. 1 hit. PF00618. RasGEF_N. 1 hit. [Graphical view] |
| PRINTS | PR00008. DAGPEDOMAIN. |
| SMART | SM00109. C1. 1 hit. SM00147. RasGEF. 1 hit. SM00229. RasGEFN. 1 hit. [Graphical view] |
| PROSITE | PS00018. EF_HAND_1. 2 hits. PS50222. EF_HAND_2. 3 hits. PS00720. RASGEF. False negative. PS50009. RASGEF_CAT. 1 hit. PS50212. RASGEF_NTER. 1 hit. PS00479. ZF_DAG_PE_1. 1 hit. PS50081. ZF_DAG_PE_2. 1 hit. [Graphical view] |
| ProtoNet | Search... |
Other Resources | |
| NextBio | 38299. |
| SOURCE | Search... |

Clusters with
