Immunoreceptors can transduce either inhibitory or activatory signals depending on ligand avidity and phosphorylation status, which is modulated by the protein kinases Lyn and Fyn. Here we show that Lyn and Fyn control immune receptor signaling status. SHP-1 tyrosine 536 phosphorylation by Lyn activates the phosphatase promoting inhibitory signaling through the immunoreceptor. By contrast, Fyn-dependent phosphorylation of SHP-1 serine 591 inactivates the phosphatase, enabling activatory immunoreceptor signaling. These SHP-1 signatures are relevant in vivo, as Lyn deficiency exacerbates nephritis and arthritis in mice, whereas Fyn deficiency is protective. Similarly, Fyn-activating signature is detected in patients with lupus nephritis, underlining the importance of this Lyn–Fyn balance. These data show how receptors discriminate negative from positive signals that respectively result in homeostatic or inflammatory conditions.