Identification of a novel ligand-receptor pair constitutively activated byras oncogenes

The Ras signaling pathway is thought to control the expression of a subset of yet to be defined genes that are crucial for cell growth and differentia tion. Here we have identified by differential display a novel oncogenic Ras target, mob-5, encoding a 23-kDa cytokine-like secreted protein. Mob-5 exp ression could be induced by oncogenic Ha-ras and Ki-ras, but not by normal ras activation. Inhibitors of both Ha-Ras and mitogen-activated protein kin ase kinase completely abolished the mob-5 expression in ras transformed cel ls, with concomitant loss of the transformation phenotype. Using an alkalin e phosphatase-tagged Mob-5 as ligand, a putative Mob-5 receptor was identif ied on the cell surface of oncogenic ras transformed cells. Thus, the Mob-5 /Mob-5 receptor may represent a novel putative autocrine loop coordinately activated by ras oncogenes.