Antigen receptor ITAMs provide tonic signaling by acting as guanine nucleotide exchange factors to directly activate R-RAS2.

The small GTPase R-RAS2 regulates homeostatic proliferation and survival of T and B lymphocytes and, when present in high amounts, drives the development of B cell chronic lymphocytic leukemia. In normal and leukemic lymphocytes, R-RAS2 constitutively binds to antigen receptors through their immunoreceptor tyrosine-based activation motifs (ITAMs) and promotes tonic activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway. Here, we examined the molecular mechanisms underlying this direct interaction and its consequences for R-RAS2 activity. R-RAS2 exhibited direct, high-affinity interactions with ITAM peptides derived from B and T cell receptors through a proline-rich sequence in the hypervariable domain of R-RAS2. In resting T and B cells, the presence of antigen receptors at the plasma membrane was sufficient to promote the activation of R-RAS2 and PI3K, and mutations that abolished the interaction of R-RAS2 with ITAMs reduced R-RAS2 signaling. Binding to ITAMs increased GDP-GTP exchange on R-RAS2 through a mechanism distinct from that by which conventional cytosolic guanosine nucleotide exchange factors (GEFs) activate RAS proteins. These results define antigen receptors as noncanonical GEFs involved in the basal activation state of R-RAS2 in lymphocytes. Such a mechanism may underlie the leukemic transformation of B cells that occurs when wild-type R-RAS2 is present in high amounts.