RASGRP1 explained

RAS guanyl-releasing protein 1 is a protein that in humans is encoded by the RASGRP1 gene.^{[1] [2] [3]}

Function

RAS guanyl nucleotide-releasing protein (RASGRP) is a member of a family of genes characterized by the presence of a Ras superfamily guanine nucleotide exchange factor (GEF) domain. It functions as a diacylglycerol (DAG)-regulated nucleotide exchange factor specifically activating Ras through the exchange of bound GDP for GTP. It activates the Erk/MAP kinase cascade and regulates T-cells and B-cells development, homeostasis and differentiation.^[3]

Gene

Alternatively spliced transcript variants encoding different isoforms have been identified. The corresponding rat gene rbc7, which lacks a 5-prime exon, represents a 5-prime and 3-prime truncated version of a larger normal rat transcript that encodes a predicted 90-kD protein. This shorter transcript has not been found in humans.

Clinical significance

In November 2016 a 12-year-old patient was hospitalized for repetitive infections. Scientists have assumed that a genetic problem might be the reason. More specifically, the genetic cause is a defect of the RASGRP1 gene which makes it inactive. .

RASGRP1 plays a role in the functions of natural killer cell dyneins. Since dyneins are motor proteins, their function is to circulate the elements inside the cells. Dr. Orange's laboratory studies have established a functional link between the defects of natural killer cells and dyneins, which in combination with Other observations led doctors to try the drug lenalidommide to treat the patient. The drug was able to reverse certain effects of the mutation RASGRP1.

Further reading

• Dower NA, Stang SL, Bottorff DA, Ebinu JO, Dickie P, Ostergaard HJ, Stone JC . RasGRP is essential for mouse thymocyte differentiation and TCR signaling. . Nature Immunology . 1 . 4 . 317–21 . 2000 . 11017103 . 10.1038/79766 . 7724240 .
• Priatel JJ, Teh SJ, Dower NA, Stone JC, etal . RasGRP1 Transduces Low-Grade TCR Signals Which Are Critical For T Cell Development, Homeostasis and Differentiation. . Immunity . 17 . 5 . 617–27 . 2002 . 12433368 . 10.1016/S1074-7613(02)00451-X . free .
• Priatel JJ, Chen X, Zenewicz LA, Shen H, Harder KW, Horwitz MS, etal . Chronic Immunodeficiency in Mice Lacking RasGRP1 Results in CD4 T Cell Immune Activation and Exhaustion. . J. Immunol. . 179 . 4 . 2143–52 . 2007 . 17675473 . 10.4049/jimmunol.179.4.2143. free .
• Priatel JJ, Chen X, Dhanji S, Abraham N, etal . RasGRP1 Transmits Pro-Differentiation TCR Signaling that is Crucial for CD4 T Cell Development. . J. Immunol. . 177 . 3 . 1470–80 . 2006 . 16849453 . 10.4049/jimmunol.177.3.1470. free .
• Priatel JJ, Chen X, Huang YH, Chow MT, Zenewicz LA, Coughlin JJ, Shen H, Stone JC, Tan R, etal . RasGRP1 regulates antigen-induced developmental programming by naive CD8 T cells. . J. Immunol. . 184 . 2 . 666–76 . 2010 . 20007535 . 10.4049/jimmunol.0803521. free .
• Ebinu JO, Bottorff DA, Chan EY, etal . RasGRP, a Ras guanyl nucleotide- releasing protein with calcium- and diacylglycerol-binding motifs. . Science . 280 . 5366 . 1082–6 . 1998 . 9582122 . 10.1126/science.280.5366.1082 . 1998Sci...280.1082E .
• Topham MK, Prescott SM . Diacylglycerol kinase zeta regulates Ras activation by a novel mechanism. . J. Cell Biol. . 152 . 6 . 1135–43 . 2001 . 11257115 . 10.1083/jcb.152.6.1135 . 2199204 .
• Strausberg RL, Feingold EA, Grouse LH, etal . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . free .
• Bivona TG, Pérez De Castro I, Ahearn IM, etal . Phospholipase Cgamma activates Ras on the Golgi apparatus by means of RasGRP1. . Nature . 424 . 6949 . 694–8 . 2003 . 12845332 . 10.1038/nature01806 . 2003Natur.424..694B . 4403046 .
• Madani S, Hichami A, Cherkaoui-Malki M, etal . Diacylglycerols containing Omega 3 and Omega 6 fatty acids bind to RasGRP and modulate MAP kinase activation. . J. Biol. Chem. . 279 . 2 . 1176–83 . 2004 . 14583629 . 10.1074/jbc.M306252200 . free .
• Klinger MB, Guilbault B, Goulding RE, Kay RJ . Deregulated expression of RasGRP1 initiates thymic lymphomagenesis independently of T-cell receptors. . Oncogene . 24 . 16 . 2695–704 . 2005 . 15829980 . 10.1038/sj.onc.1208334 . 23262099 .
• Liu Y, Zhu M, Nishida K, etal . An essential role for RasGRP1 in mast cell function and IgE-mediated allergic response. . J. Exp. Med. . 204 . 1 . 93–103 . 2007 . 17190838 . 10.1084/jem.20061598 . 2118421 .
• Roose JP, Mollenauer M, Ho M, etal . Unusual interplay of two types of Ras activators, RasGRP and SOS, establishes sensitive and robust Ras activation in lymphocytes. . Mol. Cell. Biol. . 27 . 7 . 2732–45 . 2007 . 17283063 . 10.1128/MCB.01882-06 . 1899892 .
• Ewing RM, Chu P, Elisma F, etal . Large-scale mapping of human protein-protein interactions by mass spectrometry. . Mol. Syst. Biol. . 3 . 1. 89 . 2007 . 17353931 . 10.1038/msb4100134 . 1847948 .
• Pasvolsky R, Feigelson SW, Kilic SS, etal . A LAD-III syndrome is associated with defective expression of the Rap-1 activator CalDAG-GEFI in lymphocytes, neutrophils, and platelets. . J. Exp. Med. . 204 . 7 . 1571–82 . 2007 . 17576779 . 10.1084/jem.20070058 . 2118641 .
• Kosco KA, Cerignoli F, Williams S, etal . SKAP55 modulates T cell antigen receptor-induced activation of the Ras-Erk-AP1 pathway by binding RasGRP1. . Mol. Immunol. . 45 . 2 . 510–22 . 2007 . 17658605 . 10.1016/j.molimm.2007.05.024 .
• Yasuda S, Stevens RL, Terada T, etal . Defective expression of Ras guanyl nucleotide-releasing protein 1 in a subset of patients with systemic lupus erythematosus. . J. Immunol. . 179 . 7 . 4890–900 . 2007 . 17878389 . 10.4049/jimmunol.179.7.4890. free .

Notes and References

1. Bottorff D, Ebinu J, Stone JC . RasGRP, a Ras activator: mouse and human cDNA sequences and chromosomal positions . Mamm Genome . 10 . 4 . 358–61 . May 1999 . 10087292 . 10.1007/s003359901001 . 34266456 .
2. Kawasaki H, Springett GM, Toki S, Canales JJ, Harlan P, Blumenstiel JP, Chen EJ, Bany IA, Mochizuki N, Ashbacher A, Matsuda M, Housman DE, Graybiel AM . A Rap guanine nucleotide exchange factor enriched highly in the basal ganglia . Proc Natl Acad Sci U S A . 95 . 22 . 13278–83 . Nov 1998 . 9789079 . 23782 . 10.1073/pnas.95.22.13278 . 1998PNAS...9513278K . free .
3. Web site: Entrez Gene: RASGRP1 RAS guanyl releasing protein 1 (calcium and DAG-regulated).