RAS guanyl-releasing protein 1 (Ras guanyl-releasing protein, Ca+2 & DAG-regulated guanine nucleotide exchange factor II, calDAG-GEFII, RASGRP1, RASGRP)
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Function
- 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 & B-lymphocytes antigen receptors to the activation of Ras
- hence, regulates T-cells & B-cells development, homeostasis & differentiation
- functions also in FcERI-evoked degranulation & cytokine secretion by mast cells, regulating allergic response
- may also function in other cell types differentiation forms a signaling complex with DGKZ & HRAS
- interacts with F-actin
- interacts with SKAP1
- probably regulated by Ca+2 (putative)
- regulated by PLC gamma, DGKA, DGKZ & by F-actin polymerization
Structure
- phorbol-ester/DAG-type Zn+2 finger is the principal mediator of the targeting to membranes & is required for functional activation through DAG-binding
- belongs to the RASGRP family
- contains 2 EF-hand domains
- contains 1 N-terminal Ras-GEF domain
- contains 1 phorbol-ester/DAG-type Zn+2 finger
- contains 1 Ras-GEF domain
Compartment
- cytoplasm, peripheral membrane, cell membrane
- Golgi apparatus, endoplasmic reticulum
- found both in the cytosol & 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 & dendrites but not to axons of hippocampal pyramidal cells
Alternative splicing
- named isoforms=5
- additional isoforms seem to exist
- several splicing events may be used independently in a modular way
Expression
- expressed in brain with higher expression cerebellum, cerebral cortex & amygdala
- expressed in the hematopoietic system
- expressed in T-cells (at protein level)
- expressed in fetal brain & kidney
Pathology
- altered expression of the different RASGRP1 isoforms may be a cause of susceptibility to systemic lupus erythematosus