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The presence of an immunoreceptor tyrosine-based activation motif (ITAM) makes immunoreceptors different from other signaling receptors, like integrins, G-coupled protein receptors, chemokine receptors, and growth factor receptors. This unique motif has the canonical sequence D/Ex0–2YxxL/Ix6–8YxxL/I, where x represents any amino acid and is present at least once in all immunoreceptor complexes. Immunoreceptors can promote survival, activation, and differentiation by transducing signals through these highly conserved motifs. Traditionally, ITAM signaling is thought to occur in response to ligand-induced aggregation, although evidence indicates that ligand-independent tonic signaling also provides functionally relevant signals. The majority of proteins containing ITAMs are transmembrane proteins that exist as part of immunoreceptor complexes. However, oncogenic viruses also have ITAM-containing proteins. In this review, we discuss what is known about tonic signaling by both cellular and viral ITAM-containing proteins and speculate what we might learn from each context. [ABSTRACT FROM AUTHOR]