Abstract 4274: Prolidase directly binds and activates epidermal growth factor receptor and stimulates downstream signaling.

Abstract

Abstract Prolidase, also known as Xaa-Pro dipeptidase or peptidase D (PEPD), is a ubiquitously expressed enzyme that hydrolyzes dipeptides with proline or hydroxyproline at the carboxy terminus. Unexpectedly, we have found that recombinant human PEPD directly binds and activates epidermal growth factor receptor (EGFR), and that EGFR activation by PEPD in turn leads to activation of multiple signaling molecules downstream of EGFR, including but may not be limited to AKT, ERK and STAT3. EGFR is a cell surface receptor that plays a major role in a variety of cellular responses, and EGFR activation is known to result in increase in DNA synthesis, cell growth, cell proliferation and cell migration, which perhaps are most clearly demonstrated in cancer cells. The ability of PEPD to activate EGFR signaling is neither cell-specific nor dependent on its enzymatic activity; in the latter case, an enzymatically inactive PEPD mutant was similarly effective in activating EGFR, AKT, ERK and STAT3. PEPD is also a novel inducer of cyclooxygenase-2 (Cox-2), known to play an important role in cancer, inflammation and other diseases, but Cox-2 induction by PEPD also depends on EGFR activation. In line with the pro-survival and pro-proliferation activities of EGFR and Cox-2, PEPD stimulates cell proliferation and DNA synthesis in cultured cells. However, PEPD could activate EGFR only when it was present in the extracellular space, as forced expression of human PEPD via transient gene transfection failed to activate EGFR and the downstream signaling proteins. This result is nonetheless consistent with EGFR being a cell surface receptor. Although PEPD is normally a cytosolic protein, it is apparently released from injured cells and tissues in vivo, and such release appears to result in EGFR activation and activation of its downstream signals. PEPD differs from all known EGFR ligands in that it does not possess an epidermal growth factor (EGF) motif and is not synthesized as a transmembrane precursor. Indeed, there are several notable differences between PEPD and EGF with regard to binding and activation of EGFR and activation of downstream signaling molecules. In conclusion, PEPD is a new ligand of EGFR and presents a novel mechanism of EGFR activation. Citation Format: Lu Yang. Prolidase directly binds and activates epidermal growth factor receptor and stimulates downstream signaling. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4274. doi:10.1158/1538-7445.AM2013-4274