Antigen receptors on B and T lymphocytes transduce signals by activating nonreceptor protein tyrosine kinases (PTKs). A family of receptor PTKs contains kinase insert regions with the sequence tyrosine-X-X-methionine (where X is any amino acid) that when phosphorylated mediate the binding and activation of phosphatidylinositol 3-kinase (PI 3-kinase). The CD19 membrane protein of B cells enhances activation through membrane immunoglobulin M (mIgM) and was found to contain a functional analog of the kinase insert region. Ligation of mIgM induced phosphorylation of CD19 and association with PI 3-kinase. Thus, CD19 serves as a surrogate kinase insert region for mIgM by providing the means for PI 3-kinase activation by nonreceptor PTKs.