Schematic presentation of the probable mechanism of induction of Lck through the GCR and CD45. Under resting T-cell conditions, Lck is attached to the CD4 molecules and Zap70 is associated with the TCR. CD45, the membrane-bound phosphatase molecule, is localized to the plasma membrane keeping its interactive domain toward the cytosol. Fyn and downstream small GTPase molecules, such as Rac1 and Vav, are also present in the cytosol. All of these molecules are not phosphorylated in their inactive resting state. On DM treatment, we think that the GCR, on ligation with DM in resting T cells interacts with CD45 molecule, which may in turn influence its ability to localize with and/or bind to the CD4-bound Lck possibly facilitating its release because of phosphorylation.^50–54 CD45 differentially regulates the negatively acting pTyr-505 and positively acting pTyr-394 p56^lck tyrosine kinase phosphorylation sites. We propose that DM facilitates CD45 dephosphorylation of p56^lck pTyr-394. Our data have revealed that there appears to be a physical association between these 3 molecules in response to DM treatment. Although how and where these molecules actually interface remain to be defined, activated Lck stimulates Fyn59, which in turn phosphorylates Zap70. Activated Src kinases initiate the activation of small GTPases, Rac1 and Vav, which ultimately promote actin polymerization and cell migration. This phenomenon also appears to occur in the presence of CXCL12 and is further augmented when these mediators are combined. The activation of Lck on treatment of resting T cells with CXCL12 may be involved in orchestrating the downstream signaling pathways necessary for chemotaxis.^18,19  CXCR4 has been shown to physically associate with the TCR on CXCL12 ligation and uses the ZAP70-binding ITAM domains of the TCR for signal transduction.²⁰  This association may actually account for several activities attributed to CXCR4 activation, including MAP kinase activation, intracellular calcium mobilization, enhanced activator protein-1 activity, and cytokine production. Such an association may also account for the similar TCR-like signals observed in response to CXCL12 treatment. On treatment with DM, the combined DM-CXCL12-mediated effect on Lck, Rac, and Vav activation and actin polymerization may account for the augmented CXCR4-mediated signaling and responses in the presence of DM. Moreover, these data also demonstrate an as-yet undescribed role for GCR in T-cell signaling.