Extracellular localization of epimorphin/syntaxin-2

To the editor:

In a recent article, Flaumenhaft et al¹  showed that syntaxin-2 is found on the extracellular cell surface on activated platelets. While they conclude that theirs is the first demonstration of extracellular presentation of a syntaxin molecule, it should be noted that the syntaxin-2 protein is identical to epimorphin, which was identified first in 1992 as an extracellular morphogen through the use of function-blocking antibodies in lung and skin organ culture assays²  and then in 1993 renamed as syntaxin-2, a member of the SNARE family of proteins that mediates intracellular vesicle fusion.³  As an extracellular morphogen, epimorphin has been found to be associated with the extracellular cell surface and also as a secreted molecule, acting to influence developmental processes of a wide variety of tissues including lung, mammary gland, liver, intestine, pancreas, cartilage, and hair follicle.^2,4-8 

The function of platelet cell surface epimiorphin/syntaxin-2 is unclear. In the cytoplasm, epimorphin/syntaxin-2 is localized to the inner surface of the plasma membrane as a target SNARE (t-SNARE) and acts to mediate fusion with vesicles that possess the appropriate vesicle SNARE (v-SNARE) proteins.⁹  Flaumenhaft et al¹  suggest that platelet cell surface epimorphin/syntaxin-2 may play a role analogous with its intracellular function, perhaps by mediating cell-cell fusion events. To accomplish this, the target cells would also need to present extracellular v-SNARE proteins and, to date, there are no indications for extracellular presentation of v-SNARE proteins. Another possibility is that platelet cell surface epimorphin/syntaxin-2 may function as an adhesive or signaling molecule, as it functions in many other cell types.^2,4-7  Epimorphin/syntaxin-2 has been found to bind αVβ5 and αVβ1 integrins on target epithelial cells and to initiate specific signaling processes¹⁰ ; platelet cell surface epimorphin may similarly facilitate adhesion and/or cell signaling processes with endothelial or other cell types through association with cell surface integrins on these target cells. In either case, the recent studies of Flaumenhaft et al are a key first step in the elucidation of platelet-specific functions controlled by this intriguing molecule.