RAS guanyl releasing protein 1 | EF-hand domain containing proteins | IUPHAR Guide to IMMUNOPHARMACOLOGY

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RAS guanyl releasing protein 1

Target id: 3016

Nomenclature: RAS guanyl releasing protein 1

Family: EF-hand domain containing proteins

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

   GtoImmuPdb view: ON :     RAS guanyl releasing protein 1 has curated data in GtoImmuPdb

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 797 15q14 RASGRP1 RAS guanyl releasing protein 1
Mouse - 795 2 E5; 2 59.19 cM Rasgrp1 RAS guanyl releasing protein 1
Rat - 795 3q35 Rasgrp1 RAS guanyl releasing protein 1
Gene and Protein Information Comments
The human gene gives rise to alternatively spliced transcript variants that encode different protein isoforms. Isoform a is the longest at 797 amino acids, and isoforms b and c are shorter proteins.
Previous and Unofficial Names
calcium- and diacylglycerol-regulated guanine nucleotide exchange factor II | CalDAG-GEFII | RASGRP | RAS guanyl releasing protein 1 (calcium and DAG-regulated)
Database Links
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia

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Activators
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Ligand Sp. Action Affinity Units Reference
RasGRP activator 1 Hs Binding 9.6 pKi 1
pKi 9.6 (Ki 2.5x10-10 M) [1]
Description: Displacement of [3H]PDBu from the DAG-responsive C1 domain of recombinant RasGRP1.
Immunopharmacology Comments
RAS guanyl releasing protein 1 (RASGRP1) functions as a diacylglycerol (DAG)-regulated nucleotide exchange factor. It activates Ras and the downstream Erk/MAP kinase cascade. RASGRP1 regulates the development, homeostasis and differentiation of T aand B cells [2,7,10], and has been linked to NK cell development and function [4,10]. Loss-of-function mutations in RASGRP1 have been identified in patients with early onset primary immunodeficiency and a predisposition to lymphoproliferative disease [5-6,11-12]. Autoimmune pathology has also been reported as a consequence of defective RASGRP1 function [3,13].[9].
Physiological Consequences of Altering Gene Expression
RasGRP1(-/-) mice develop chronic immunodeficiency that is characterised by spontaneous development of acutely activated and proliferating CD4 T cells and T cell exhaustion.
Species:  Mouse
Tissue: 
Technique: 
References:  8
Gene Expression and Pathophysiology Comments
Biallelic loss-of-function mutations in RASGRP1 have been identified in patients presenting with early onset primary immunodeficiency and a predisposition to lymphoproliferative disease ( e.g. Epstein-Barr virus (EBV)-associated B cell lymphoma) [5-6,11-12].

References

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1. Garcia LC, Donadío LG, Mann E, Kolusheva S, Kedei N, Lewin NE, Hill CS, Kelsey JS, Yang J, Esch TE et al.. (2014) Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP. Bioorg. Med. Chem., 22 (12): 3123-40. [PMID:24794745]

2. Golec DP, Henao Caviedes LM, Baldwin TA. (2016) RasGRP1 and RasGRP3 Are Required for Efficient Generation of Early Thymic Progenitors. J. Immunol., 197 (5): 1743-53. [PMID:27465532]

3. Layer K, Lin G, Nencioni A, Hu W, Schmucker A, Antov AN, Li X, Takamatsu S, Chevassut T, Dower NA et al.. (2003) Autoimmunity as the consequence of a spontaneous mutation in Rasgrp1. Immunity, 19 (2): 243-55. [PMID:12932358]

4. Lee SH, Yun S, Lee J, Kim MJ, Piao ZH, Jeong M, Chung JW, Kim TD, Yoon SR, Greenberg PD et al.. (2009) RasGRP1 is required for human NK cell function. J. Immunol., 183 (12): 7931-8. [PMID:19933860]

5. Mao H, Yang W, Latour S, Yang J, Winter S, Zheng J, Ni K, Lv M, Liu C, Huang H et al.. (2018) RASGRP1 mutation in autoimmune lymphoproliferative syndrome-like disease. J. Allergy Clin. Immunol., 142 (2): 595-604.e16. [PMID:29155103]

6. Platt CD, Fried AJ, Hoyos-Bachiloglu R, Usmani GN, Schmidt B, Whangbo J, Chiarle R, Chou J, Geha RS. (2017) Combined immunodeficiency with EBV positive B cell lymphoma and epidermodysplasia verruciformis due to a novel homozygous mutation in RASGRP1. Clin. Immunol., 183: 142-144. [PMID:28822832]

7. Priatel JJ, Chen X, Huang YH, Chow MT, Zenewicz LA, Coughlin JJ, Shen H, Stone JC, Tan R, Teh HS. (2010) RasGRP1 regulates antigen-induced developmental programming by naive CD8 T cells. J. Immunol., 184 (2): 666-76. [PMID:20007535]

8. Priatel JJ, Chen X, Zenewicz LA, Shen H, Harder KW, Horwitz MS, Teh HS. (2007) Chronic immunodeficiency in mice lacking RasGRP1 results in CD4 T cell immune activation and exhaustion. J. Immunol., 179 (4): 2143-52. [PMID:17675473]

9. Rapoport MJ, Bloch O, Amit-Vasina M, Yona E, Molad Y. (2011) Constitutive abnormal expression of RasGRP-1 isoforms and low expression of PARP-1 in patients with systemic lupus erythematosus. Lupus, 20 (14): 1501-9. [PMID:21976405]

10. Shen S, Chen Y, Gorentla BK, Lu J, Stone JC, Zhong XP. (2011) Critical roles of RasGRP1 for invariant NKT cell development. J. Immunol., 187 (9): 4467-73. [PMID:21957144]

11. Somekh I, Marquardt B, Liu Y, Rohlfs M, Hollizeck S, Karakukcu M, Unal E, Yilmaz E, Patiroglu T, Cansever M et al.. (2018) Novel Mutations in RASGRP1 are Associated with Immunodeficiency, Immune Dysregulation, and EBV-Induced Lymphoma. J. Clin. Immunol., 38 (6): 699-710. [PMID:30030704]

12. Winter S, Martin E, Boutboul D, Lenoir C, Boudjemaa S, Petit A, Picard C, Fischer A, Leverger G, Latour S. (2018) Loss of RASGRP1 in humans impairs T-cell expansion leading to Epstein-Barr virus susceptibility. EMBO Mol Med, 10 (2): 188-199. [PMID:29282224]

13. Yasuda S, Stevens RL, Terada T, Takeda M, Hashimoto T, Fukae J, Horita T, Kataoka H, Atsumi T, Koike T. (2007) Defective expression of Ras guanyl nucleotide-releasing protein 1 in a subset of patients with systemic lupus erythematosus. J. Immunol., 179 (7): 4890-900. [PMID:17878389]

How to cite this page

EF-hand domain containing proteins: RAS guanyl releasing protein 1. Last modified on 28/08/2018. Accessed on 15/12/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=3016.