N-terminal cleaved pancreatitis-associated protein-III (PAP-III) serves as a scaffold for neurites and promotes neurite outgrowth.

Pancreatitis-associated protein (PAP)-III, also known as regenerating gene/regenerating islet-derived (Reg)-IIIγ, is a small secretory protein whose expression is substantially induced in injured nerves. Here, we found that PAP-III protein underwent proteolytic N-terminal processing by trypsin-like protease(s) in injured sciatic nerves after axotomy. In vitro studies demonstrated that the N terminus-truncated PAP-III (ΔN-PAP-III) polymerized into a filament with a relatively uniform diameter of 10-20 nm, and the filaments formed higher order structures in a Na(+) concentration-dependent manner. When the ΔN-PAP-III fibers were added to the culture media, the ΔN-PAP-III fibers were tightly attached to neurites and somata of primary cortical neurons in vitro. In contrast, little association with glial cells was observed. When dense matrices of ΔN-PAP-III fibers were sheeted on a culture dish, neurites preferentially adhered to the fibers, and neurite extension was enhanced. This neurite outgrowth activity was significantly suppressed by preincubation with antibodies against PAP-III. These results imply that the released PAP-III might be cleaved and forms ΔN-PAP-III fibers at the nerve injury sites. Consequently, these resulting fibers would provide regenerating axons with a platform for extension.