The normal myeloid hematopoietic regulatory proteins include 4 different growth-inducing proteins (IL-3, MGI-1GM = GM-CSF, MGI-1G = G-CSF, and MGI-1M = M-CSF = CSF-1). There is also another type of normal myeloid regulatory protein (MGI-2) with no MGI-1 (CSF or IL-3) activity, which can induce differentiation of normal myeloid precursors and certain clones of myeloid leukemic cells. Studies on the binding of MGI-2 to differentiation-competent (D+) and differentiation-defective (D-) clones of mouse myeloid leukemic cells and to normal cells indicate that: (1) D+ clones of myeloid leukemic cells had about 2,500 high-affinity surface receptors per cell, like mature normal myeloid cells, and the bound MGI-2 was rapidly internalized with its cell-surface receptors at 37 degrees C causing down-regulation of MGI-2 receptors in both the normal and leukemic cells; (2) in some D- clones, the number and internalization of MGI-2 receptors were similar to those of D+ clones whereas other D- clones had only 0-100 MGI-2 receptors per cell; (3) normal thymus and lymph-node lymphocytes and T lymphoma cells did not show detectable MGI-2 receptors; (4) there was an independent expression of receptors for MGI-2 and for the 4 myeloid growth-inducing proteins on different clones of myeloid leukemic cells; and (5) none of the 4 myeloid growth-inducing proteins IL-3, MGI-1GM, MGI-1G, or MGI-1M, inhibited binding of MGI-2 to its receptors. The cytotoxic proteins lymphotoxin and tumor necrosis factor did not induce differentiation of the mouse myeloid leukemic cells and also did not inhibit binding of MGI-2 to its receptors. These results show that the myeloid differentiation-inducing protein MGI-2 binds to cell-surface receptors that are different from the receptors for the 4 myeloid growth-inducing proteins and these cytotoxic proteins.