The immune system must maintain a delicate balance between the positive signals that activate lymphocytes and the negative signals that dampen inappropriate immune responses. If this balance is upset, the immune system either does not respond to pathogens or responds inappropriately, resulting in autoimmune disease. Antigens, cytokines, and death-inducing members of the tumor necrosis factor (TNF) family (1, 2) all contribute to homeostatic regulation of the immune system. Several recent reports, including one by Lu and Lemke (3) on page 306 of this issue, now implicate the Tyro-3 family of receptor tyrosine kinases as important players in immune regulation. The Tyro-3 family (Tyro-3, Axl, and Mer) may fine-tune the immune response by modulating the activity of macrophages and other antigen-presenting cells (APCs) that present antigen to T and B lymphocytes (3–5).

The Tyro-3 receptor tyrosine kinases have an extracellular region composed of two immunoglobulin-like domains and two fibronectin-like domains, and an intracellular kinase domain that contains a distinctive Lys-Trp-Ile-Ala-Ile-Glu-Ser motif [reviewed in (6)]. These receptors are overexpressed by many tumors and can transform (immortalize) cultured cells in vitro, suggesting that they provide positive growth-promoting signals to cells. They activate Src family kinases and signaling pathways downstream of Grb2 (an adapter protein in the Ras pathway), promoting cell proliferation and protecting against programmed cell death (apoptosis). The ligands for these receptors, protein S (an anticoagulant) and Gas6, are expressed by many cell types and share similarities with sex hormone-binding globulin. Although the Tyro-3 receptors and their ligands have been well characterized, the signaling pathways that they activate are poorly understood.