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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.<\/jats:p>","DOI":"10.1126\/scisignal.adk4204","type":"journal-article","created":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T18:58:36Z","timestamp":1738090716000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":3,"title":["Antigen receptor ITAMs provide tonic signaling by acting as guanine nucleotide exchange factors to directly activate R-RAS2"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9451-2888","authenticated-orcid":true,"given":"Alejandro M.","family":"Hortal","sequence":"first","affiliation":[{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa, Consejo Superior de Investigaciones Cient\u00edficas, Universidad Aut\u00f3noma de Madrid, 28049 Madrid, 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