In this study, we report a novel gene, CCDC134 (coiled-coil domain containing 134), that encodes a secretory protein that can inhibit the MAPK pathway as a novel human MAPK-regulating protein. The CCDC134 mRNA contains 1280 nucleotides, encoding a protein of 229 amino acids. CCDC134 is a classical secretory protein. Expression profile analysis by Northern blot, RT-PCR, immunohistochemistry and Western blot reveals that CCDC134 is widely expressed in normal adult tissues, tumor tissues and cell lines. Functional investigation reveals that overexpression of CCDC134 and its purified protein significantly inhibit transcriptional activity of Elk1 and phosphorylation of Erk and JNK/SAPK but not p38 MAPK. Conversely, specific siRNA against CCDC134 activates Elk1 transcriptional activity and promotes Erk and JNK/SAPK phosphorylation. These results clearly indicate that CCDC134 is a novel member of the secretory family and down-regulates the Raf-1/MEK/ERK and JNK/ SAPK pathways.