RasGRP1

Ras guanyl nucleotide-releasing protein 1 (RasGRP1) is a cytosolic guanine nucleotide exchange factor (GEF) that activates Ras family GTPases by promoting the exchange of GDP for GTP. It is a member of the RasGRP family and is activated by signals that raise intracellular calcium and diacylglycerol (DAG). In humans, RASGRP1 is expressed predominantly in hematopoietic cells, especially T and B lymphocytes.

RasGRP1 contains structural domains that support its function, including EF-hand calcium-binding motifs, a diacylglycerol (DAG)-binding C1 domain, and a catalytic RasGEF domain related to CDC25. In response to receptor signaling, phospholipase C gamma generates IP3 and DAG. Calcium elevations bind the EF-hands and DAG binds the C1 domain, relieving autoinhibition and promoting the translocation of RasGRP1 to the plasma membrane where it facilitates GDP-to-GTP exchange on Ras. Activated Ras then triggers the RAF-MEK-ERK MAPK signaling cascade, leading to changes in gene expression that govern T and B cell activation and proliferation.

Biological roles of RasGRP1 are prominent in immune cell signaling. It is essential for normal thymocyte development and T cell maturation, with genetic disruption causing impaired Ras-ERK signaling and defective T cell development in experimental models. RasGRP1 also participates in peripheral T cell activation and contributes to B cell signaling.

Clinical relevance is an area of active research. Dysregulation of RasGRP1 function has been linked to immune system disorders and certain hematologic malignancies, where aberrant Ras signaling can influence disease progression.