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we here describe a novel mutation in RASGRP2 that affects both expression and function of CalDAG-GEFI (show RASGRP1 Proteins) and that causes impaired platelet adhesive function and significant bleeding in humans.
Eleven cases with unexplained bleeding or platelet disorders harbored 11 different, previously unreported RASGRP2 variants that were biallelic and likely pathogenic.
These patients are the first cases of a CalDAG-GEFI (show RASGRP1 Proteins) deficiency due to homozygous RASGRP2 mutations that are linked to defects in both leukocyte and platelet integrin activation.
These studies identify RasGRP2 as a novel substrate of ERK1/2 and define a negative-feedback loop that regulates the BRaf-MEK-ERK signaling cascade. This negative-feedback loop determines the amplitude and duration of active ERK1/2.
RasGRP2 is exceptional in that its C1 domain has very weak binding affinity (Kd = 2890 +/- 240 nm for [(3)H]phorbol 12,13-dibutyrate. We have identified four amino acid residues responsible for this lack of sensitivity. Replacing Asn(7), Ser (show SIGLEC1 Proteins)(8), Ala(19), and Ile(21) with the corresponding residues from RasGRP1 (show RASGRP1 Proteins)/3 (Thr (show TRH Proteins)(7), Tyr (show TYR Proteins)(8), Gly(19), and Leu(21), respectively) conferred potent binding affinity (Kd = 1.47 +/- 0.03 nm).
Human CalDAG-GEFI (show RASGRP1 Proteins) gene (RASGRP2) mutation affects platelet function and causes severe bleeding.
phosphorylation of CalDAG-GEFI (show RASGRP1 Proteins) is a critical mechanism by which PKA controls Rap1b (show RAP1B Proteins)-dependent platelet aggregation
RasGRP2 increases cell viability and cell-matrix adhesion through increased Ras expression and Rap1 activation, respectively, in endothelial cells.
NIH3T3 cells were found nonpermissive to mtHSV but they became permissive following transformation with the Rasgrp2 gene. This effect was linked to the activation of the Ras-PKR (show PKLR Proteins) signaling pathway.
analyzed the 5'-flanking region of rasgrp2 gene by a luciferase assay, which revealed that not only a promoter but also silencer regions were present upstream of D1E, suggesting rasgrp2 expression is controlled by a combination of promotion and repression
CalDAG-GEFI is critical for atherosclerotic plaque development in hypercholesterolemic Ldlr (show LDLR Proteins)(-/-) mice because of its contribution to platelet-leukocyte aggregate formation and leukocyte recruitment to the lesion area.
(i) STIM1 (show STIM1 Proteins)/SOCE is critical for procoagulant activity but not the proadhesive function of platelets; and (ii) at the site of vascular injury, STIM1 (show STIM1 Proteins) and CalDAG-GEFI are critical for the first wave of thrombin (show F2 Proteins) generation mediated by procoagulant platelets
we evaluated the contribution of CalDAG-GEFI to platelet activation in a model of immune-mediated thrombocytopenia and thrombosis syndromes
Studies indicate that CalDAG-GEFI mediates the rapid but reversible activation of integrin alphaIIbbeta3, and the adenosine diphosphate receptor P2Y12 (show P2RY12 Proteins) facilitates delayed but sustained integrin activation.
CalDAG-GEFI helps regulate neutrophil chemotaxis, independent of its established role in integrin activation, through a mechanism that involves actin cytoskeleton and cellular polarization.
In a brain-slice explant model of Huntington's disease, knock-down of CalDAG-GEFI expression rescues striatal neurons from pathology induced by transfection of polyglutamine-expanded Htt (show HTT Proteins) exon 1.
CalDAG-GEFI plays a role in inside-out signaling to alphaIIbbeta3
CalDAG-GEFI regulated the activation of beta(1) and beta(3) integrins in platelets, and CalDAG-GEFI deficiency caused complete inhibition of arterial thrombus formation.
CalDAG-GEFI and PKC represent separate, but synergizing, pathways important for alphaIIbbeta3 activation in platelets activated through the PAR4 (show F2RL3 Proteins) receptor.
The protein encoded by this gene is a brain-enriched nucleotide exchanged factor that contains an N-terminal GEF domain, 2 tandem repeats of EF-hand calcium-binding motifs, and a C-terminal diacylglycerol/phorbol ester-binding domain. This protein can activate small GTPases, including RAS and RAP1/RAS3. The nucleotide exchange activity of this protein can be stimulated by calcium and diacylglycerol. Three alternatively spliced transcript variants encoding the same protein have been found for this gene.
RAS guanyl releasing protein 2
, RAS guanyl releasing protein 2, isoform 3
, F25B3.3 kinase-like protein
, RAS guanyl nucleotide-releasing protein 2
, RAS guanyl-releasing protein 2
, calcium and DAG-regulated guanine nucleotide exchange factor I
, calcium and diacylglycerol-regulated guanine nucleotide exchange factor I
, cdc25-like protein
, guanine exchange factor MCG7
, RAS, guanyl releasing protein 2
, calcium diacylglycerol guanine nucleotide exchange factor I
, F25B3.3 kinase like protein
, RAP 1A protein-specific guanine nucleotide exchange factor 1
, RAS, guanyl releasing protein 2; RAP 1A protein-specific guanine nucleotide exchange factor 1; CalDAG-GEFI