Coupling of osteopontin and its cell surface receptor CD44 to the cell survival response elicited by interleukin-3 or granulocyte-macrophage colony-stimulating factor

The receptors for interleukin-3 (IL-3) and granulocyte-macrophage colony-st imulating factor (GM-CSF) share a common beta subunit, the distal cytoplasm ic domain of which is essential for the promotion of cell survival by these two cytokines, Genes whose expression is specifically induced by signaling through the distal cytoplasmic domain of this receptor beta subunit were s creened by a subtraction cloning approach in derivatives of a mouse pro-bet a-cell line. One gene thus identified was shown to encode a protein highly homologous (with only 7 amino acid substitutions) to murine osteopontin (OP N), a secreted adhesion protein, Conditioned medium from cells expressing w ild-type OPN, but not that from cells expressing a deletion mutant lacking residues 79 to 140, increased the viability of a non-OPN-producing cell lin e in the presence of human GM-CSF, Antibody blocking experiments revealed t hat OPN produced as a result of IL-3 or GM-CSF signaling was secreted into the medium and, through binding to its cell surface receptor, CD44, contrib uted to the survival promoting activities of these two cytokines. Furthermo re, coupling of the OPN-CD44 pathway to the survival response to IL-3 was a lso demonstrated in primary IL-3-dependent mouse hone marrow cells, These r esults thus show that induction of an extracellular adhesion protein and co nsequent activation of its cell surface receptor are important for the anti apoptotic activities of IL-3 and GM-CSF.