title: Prolidase directly binds and activates epidermal growth factor receptor and stimulates downstream signaling.
abstract: Prolidase, also known as Xaa-Pro dipeptidase or peptidase D (PEPD), is a ubiquitously expressed cytosolic enzyme that hydrolyzes dipeptides with proline or hydroxyproline at the carboxyl terminus. In this article, however, we demonstrate that PEPD directly binds to and activates epidermal growth factor receptor (EGFR), leading to stimulation of signaling proteins downstream of EGFR, and that such activity is neither cell-specific nor dependent on the enzymatic activity of PEPD. In line with the pro-survival and pro-proliferation activities of EGFR, PEPD stimulates DNA synthesis. We further show that PEPD activates EGFR only when it is present in the extracellular space, but that PEPD is released from injured cells and tissues and that such release appears to result in EGFR activation. 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, but PEPD binding to EGFR can be blocked by EGF. In conclusion, PEPD is a ligand of EGFR and presents a novel mechanism of EGFR activation.
authors.affiliation: Department of Chemoprevention, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Yang
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.forename: Yi
authors.initials: Y
authors.lastname: Ding
authors.forename: Kyoung-Soo
authors.initials: KS
authors.lastname: Choi
authors.forename: A Latif
authors.initials: AL
authors.lastname: Kazim
authors.forename: Yuesheng
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004150:Dipeptidases / Q000378:metabolism / Q000502:physiology*; D004815:Epidermal Growth Factor / Q000737:chemistry; D066246:ErbB Receptors / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D011485:Protein Binding; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D008024:Ligands; D011994:Recombinant Proteins; D004815:Epidermal Growth Factor; D051546:Cyclooxygenase 2; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D004150:Dipeptidases; C022449:proline dipeptidase