Odin is a recently identified cytosolic phosphotyrosine binding (PTB) domain containing negative regulatory protein, that was discovered on the basis of its ability to undergo tyrosine phosphorylation upon stimulation by epidermal growth factor in HeLa cells. The protein was originally obtained as a KIAA clone (KIAA 0229) from the Kazusa DNA Research Institute which maintains the HUGE protein database--a database devoted to the analysis of long cDNA clones encoding large proteins (>50 kDa). Odin has been demonstrated to cause downregulation of c-Fos promoter activity and to inhibit PDGF-induced mitogenesis in cell lines. To further investigate the role of Odin in growth factor receptor signaling and to elucidate its biological function in vivo, we have generated mice deficient in Odin by gene targeting. Odin-deficient mice do not display any obvious phenotype, and histological examination of the kidney, lung and liver does not show any major abnormalities as compared to wild-type controls. However, mouse embryonic fibroblasts (MEFs) generated from Odin-deficient mice exhibit a hyperproliferative phenotype compared to wild-type-derived MEFs, consistent with its role as a negative regulator of growth factor receptor signaling. Our results confirm that although Odin expression in mice is not essential for any major developmental pathway, it could play a significant functional role to negatively regulate growth factor receptor signaling pathways.