During the developmental and organ regenerative processes, epithelial tissues actively construct complex architectures, where their differentiation programs are spatio-temporally regulated by the surrounding stroma, so that they can effectively exert highly specialized functions in the established organs. We have focused on a morphogenic protein epimorphin, which usually exists at the cytoplasmic surface of the stromal plasma membrane and functions as a t-SNARE molecule, while is temporally secreted extracellularly and elicits local morphogenenic responses in the adjacent epithelia. By the last year, we determined molecular elements for its extracellular secretion and the signaling pathway in the target cells. This year, we tried to elucidate how its intracellular and extracellular roles are functionally related and whether other t-SNARE molecules (syntaxin 1, 3, 4, 5, 6) share such intriguing molecular nature. In addition, we investigated how epimorphin signaling impacts on the cyto-differentiation of normal keratinocytes (HaCaT). We found that 1) the domain for epimorphin's intracellular functions (SNARE domain) could determine the direction of epimorphin's vectorial secretion, 2) other membraneous t-SNARE molecules (syntaxin 3, 4,) are extracellularly secreted by the similar mechanism as that for epimorphin, and 3) the appropriate concentration gradient of epimorphin in the epidermis is critical for the epidermal keratinization program. These results indicate that epimorphin and its related molecules cooperatively play regulatory roles not only on the morphological but also on the functional differentiation in the target tissues. Recently, an important finding was reported by researchers who have focused solely on cytoplasmic functions of t-SNARE molecules, that is, the extracellular projection of epimorphin is clearly detectable in the activated platelet cells, expanding its extracellular function to hematopoietic cell types. We will further investigate the molecular mechanisms of these intriguing "double-life" proteins to establish a novel concept on the tissue morphoregulation.　(by Hirai Y.)