The dipeptidyl peptidase 4 (DPP4) family of enzymes includes DPP4, DPP8, DPP9 and Fibroblast Activation Protein (FAP). These atypical post-proline serine proteases cleave N-terminal dipeptides from their substrates. DPP4 inhibitors are in clinical use for type 2 diabetes. Fibroblast Activation Protein (FAP) is a potential cancer therapeutic target. DPP9 is intracellular and ubiquitously expressed in brain, epithelia, most lymphocytes, and some endothelial cells ¹.  DPP9 interacts with small ubiquitin-like modifier (SUMO)-1 and with H-Ras.  DPP9 enzyme activity has a novel role in upregulating epithelial cell apoptosis and downregulating proliferation via modulating the EGF/PI3K/Akt signalling pathway, as has recently been reported by our group ².

To further characterize the enzymatic function of DPP9, a gene knock-in mouse was generated with a serine to alanine point mutation at the enzyme active site (S729A). Mouse embryonic fibroblasts (MEFs) from DPP9^S729A/S729A embryonic day 13.5 and neonate DPP9^S729A/S729A mouse livers collected within 6h after birth were found to have similar DPP9 protein levels and DPP mRNA levels to wild-type, but had reduced DPP8/DPP9 derived enzyme activity, consistent with the absence of DPP9 enzyme activity. SV40 large T antigen immortalized DPP9^S729A/S729A MEFs showed no significant difference in spontaneous apoptosis, but greater apoptosis with serum starvation and greater CDDP-induced apoptosis compared to wild-type MEFs. These data show that DPP9 is anti-apoptotic in a fibroblastic cell line, which contrasts to pro-apoptotic activity of DPP9 in two epithelial hepatoma cell lines ². Thus, as we previously saw with FAP ³, cell type may be an important determinant of action in this gene family.