Serpentine membrane protein with a glycerophosphodiester phosphodiesterase (GP-PDE) motif, GDE3, is involved in morphological change of cells and accelerates the program of osteoblast differentiation, suggesting that mammalian GP-PDEs play an important role in the regulation of cytoskeletal modification. Here, we isolated two cDNAs encoding serpentine membrane proteins, GDE2 and GDE6, containing GP-PDE motif from mouse cDNA libraries. The deduced sequence of GDE2 contains 607 amino acids with seven putative transmembrane regions. GDE6 was composed of 633 amino acids also with seven putative transmembrane regions. In amino acid sequences, GDE2 and GDE6 are 43.7% and 34.3% identical to GDE3, respectively. Although GDE3 mRNA is highly expressed in bone tissue and spleen, GDE2 mRNA was expressed in a variety of mouse tissues including lung and heart, while the GDE6 transcript was particularly abundant in spermatocytes of mouse testis. Immunohistochemical analyses using anti-GDE2 antibody showed that GDE2 protein is expressed in the epithelial cell layer of mouse lung. These results suggest that GP-PDEs are differentially expressed in mouse tissues, and might have distinct roles. (C) 2004 Elsevier B.V. All rights reserved.