RASGRP2 Proteine (RASGRP2)

Human RAS Guanyl Releasing Protein 2 (Calcium and DAG-Regulated) (RASGRP2) Interaktionspartner

1. results indicate that CD38 promotes RasGRP2/Rap1-mediated CLL cell adhesion and migration by increasing intracellular Ca2+ levels.

2. we here describe a novel mutation in RASGRP2 that affects both expression and function of CalDAG-GEFI and that causes impaired platelet adhesive function and significant bleeding in humans.

3. Eleven cases with unexplained bleeding or platelet disorders harbored 11 different, previously unreported RASGRP2 variants that were biallelic and likely pathogenic.

4. These patients are the first cases of a CalDAG-GEFI deficiency due to homozygous RASGRP2 mutations that are linked to defects in both leukocyte and platelet integrin activation.

5. 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.

6. 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(8), Ala(19), and Ile(21) with the corresponding residues from RasGRP1/3 (Thr(7), Tyr(8), Gly(19), and Leu(21), respectively) conferred potent binding affinity (Kd = 1.47 +/- 0.03 nm).

7. Human CalDAG-GEFI gene (RASGRP2) mutation affects platelet function and causes severe bleeding.

8. phosphorylation of CalDAG-GEFI is a critical mechanism by which PKA controls Rap1b-dependent platelet aggregation

9. RasGRP2 increases cell viability and cell-matrix adhesion through increased Ras expression and Rap1 activation, respectively, in endothelial cells.

10. 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 signaling pathway.

11. 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

12. CalDAG-GEFI plays a role in inside-out signaling to alphaIIbbeta3

Cow (Bovine) RAS Guanyl Releasing Protein 2 (Calcium and DAG-Regulated) (RASGRP2) Interaktionspartner

1. this amino acid substitution is likely responsible for the thrombopathic phenotype observed in Simmental cattle and underscores the critical nature of this signal transduction protein in platelets

Mouse (Murine) RAS Guanyl Releasing Protein 2 (Calcium and DAG-Regulated) (RASGRP2) Interaktionspartner

1. CalDAG-GEFI is critical for atherosclerotic plaque development in hypercholesterolemic Ldlr(-/-) mice because of its contribution to platelet-leukocyte aggregate formation and leukocyte recruitment to the lesion area.

2. (i) STIM1/SOCE is critical for procoagulant activity but not the proadhesive function of platelets; and (ii) at the site of vascular injury, STIM1 and CalDAG-GEFI are critical for the first wave of thrombin generation mediated by procoagulant platelets

3. we evaluated the contribution of CalDAG-GEFI to platelet activation in a model of immune-mediated thrombocytopenia and thrombosis syndromes

4. Studies indicate that CalDAG-GEFI mediates the rapid but reversible activation of integrin alphaIIbbeta3, and the adenosine diphosphate receptor P2Y12 facilitates delayed but sustained integrin activation.

5. CalDAG-GEFI helps regulate neutrophil chemotaxis, independent of its established role in integrin activation, through a mechanism that involves actin cytoskeleton and cellular polarization.

6. 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 exon 1.

7. CalDAG-GEFI plays a role in inside-out signaling to alphaIIbbeta3

8. 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.

9. CalDAG-GEFI and PKC represent separate, but synergizing, pathways important for alphaIIbbeta3 activation in platelets activated through the PAR4 receptor.