Progranulin as a Context Dependent Signaling Molecule

Abstract

Progranulin is a signaling molecule which has roles in lysosomal function, neurodegenerative diseases, wound healing, inflammation, and proliferation. The progranulin protein is composed of 7½ highly conserved granulin repeats joined by linker regions which are subject to proteolytic processing. Thus, the ultimate biological activity of progranulin is context dependent as it relies on the relative expression of diverse intracellular and extracellular proteases and protease inhibitors. The SW13 human adrenocortical carcinoma line exists in two epigenetically distinct subtypes which both express progranulin and is therefore a uniquely powerful model in which to probe the relationship between progranulin processing and cellular activity. Treatment with low doses of exogenous progranulin increases growth of SW13‐ but not SW13+ cells. However, SW13+ cells increase their growth rate at higher progranulin doses. Together, these data are consistent with an inability of SW13+ to process endogenous progranulin to the mitogenic granulin unit(s). This conclusion is supported by immunoblotting with antibodies specific for granulin repeats revealing that progranulin is processed differently in each subtype. In this work, we focused on lysosomes as a potential site for differential processing of progranulin as lysosomal proteases have been shown to process progranulin and progranulin itself plays a role in lysosome maturation. Differences in lysosomal pH and function between the two subtypes have been detected using two pH‐sensitive dyes which localize to the lysosome. Ongoing experiments are aimed at probing the ability of differential processing of progranulin to influence which subtype the cell line adopts.