The signaling pathways linked to membrane immunoglobulin (mIg) that are regulated by the coreceptors CD19 and CD22 are not known. The mitogen-activated protein (MAP) kinases ERK2, JNK, and p38 couple extracellular signals to transcriptional responses. The capacity of mIg to activate these MAP kinases is synergistically amplified by coligating CD19, and this effect requires that CD19 be juxtaposed to mIg. CD22 suppresses MAP kinase activation when cross-linked to mIg alone or to the coligated complex of mIg and CD19. Separate ligation and sequestration of CD22 from mIg enhances MAP kinase activation, probably reflecting release of mIg from constitutive down-regulation. Thus, CD19 and CD22 have counterregulatory effects on MAP kinase activation by mIg, which are dependent on their proximity to the antigen receptor.