Regulation and Function of the RasGRP Family of Ras Activators in Blood Cells

Ras guanyl nucleotide releasing proteins (RasGRPs) are guanyl nucleotide exchange factors that activate Ras and related GTPases such as Rap. Like Sos proteins, RasGRPs have a catalytic region composed of a Ras exchange motif (REM) and a CDC25 domain. RasGRPs also possess a pair of atypical EF hands that may bind calcium in vivo and a C1 domain resembling the diacylglycerol (DAG)-binding domain of protein kinase C. DAG directly activates RasGRPs by a membrane recruitment mechanism as well as indirectly by PKC-mediated phosphorylation. RasGRPs are prominently expressed in blood cells. RasGRP1 acts downstream of TCR, while RasGRP1 and RasGRP3 both act downstream of BCR. Together, they regulate Ras in adaptive immune cells. RasGRP2, through Rap, plays a role in controlling platelet adhesion, while RasGRP4 controls Ras activation in mast cells. RasGRP malfunction likely contributes to autoimmunity and may contribute to blood malignancies. RasGRPs might prove to be viable drug targets. The intracellular site of RasGRP action and the relationship between RasGRPs and other Ras regulatory mechanisms are subjects of lively debate.