IL-24/MDA-7 is a new member of the IL-10 family of cytokines, which signals through two heterodimeric receptor complexes (IL-20R1/IL-20R2 and IL-22R/IL-20R2). Previously, we identified a rat gene named mob-5, which encodes a secreted protein that shares a high degree of homology with human IL-24. Expression of mob-5 and its putative cell surface receptors was shown to be upregulated by oncogenic ras. Here we show that not only do rat mob-5 and human IL-24 share a strikingly similar genomic structure but also that the rat MOB-5 protein can bind to and signal through the human IL-24 receptors. Like human IL-24, binding of the rat MOB-5 protein to the human IL-24 receptors leads to activation of the JAK/STAT pathway, which in turn supports receptor-dependent survival and proliferation of Ba/F3 cells. Furthermore, using human colon cancer cell lines with somatic knockout of either the mutant or the wild-type k-ras allele, we demonstrate that the human IL-24 receptors also are upregulated by oncogenic ras. Taken together, these results provide strong experimental evidence that MOB-5 is indeed the rat homolog of human IL-24.