RasGRP4 in mast cell signalling and disease susceptibility

The nucleotide sequences of the mouse, rat and human cDNAs and genes that encode the fourth member of the Ras guanine nucleotide releasing protein (RasGRP) family of signalling proteins have been deduced. RasGRP4 is a mast cell-restricted, cation-dependent, guanine nucleotide exchange factor (GEF). It is also a diacylglycerol (DAG)/phorbol ester receptor that plays a prominent role in dictating which protease and eicosanoid mediators are expressed in rodent and human mast cell lines. RasGRP4 appears to act downstream of the tyrosine kinase receptor c-Kt/CD117 and upstream of the basic-helix-loop-helix-leucine zipper transcription factor MITE Allelic variants of RasGRP4 have been identified, as have functionally different isoforms that are the result of variable splicing of its gene. Earlier gene-linkage studies revealed a site on chromosome 7A3-B1 that controls intrinsic airway reactivity to methacholine in backcrossed C3H/HeJ and A/J mice. The 18-exon mouse RasGRP4 gene resides on chromosome 7A3-B1, and recent studies revealed that the mast cells developed from the hyporesponsive C3H/HeJ mouse strain preferentially produce a defective isoform of RasGRP4. These and other data suggest that RasGRP4 is of critical importance in mast cell development and that the expression of abnormal isoforms of the protein can lead to mast cell dysfunction.