Prolidase Directly Binds and Activates Epidermal Growth Factor Receptor and Stimulates Downstream Signaling

Lu Yang,Yun Li,Yi Ding,Kyoung-Soo Choi,A Latif Kazim,Yuesheng Zhang

doi:10.1074/jbc.m112.429159

Lu Yang, Yun Li + Show 4 more

Open Access

https://doi.org/10.1074/jbc.m112.429159

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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.

Highlights

All known ligands of epidermal growth factor (EGF) receptor (EGFR) are characterized by the EGF motif and generated from transmembrane precursors
We demonstrate that peptidase D (PEPD), which we initially identified as an inducer of cyclooxygenase-2 (Cox-2), is a ligand of EGF receptor (EGFR) and that EGFR activation by PEPD leads to stimulation of signaling proteins downstream of EGFR and induction of Cox-2
PEPD Induces Cox-2, and It Does So without Requiring Its Dipeptidase Activity but Only When Present in the Extracellular Space—Cox-2 plays a key role in the biosynthesis of prostaglandins, which act as autocrine and paracrine signaling molecules that are important for a variety of biological activities [15]

Summary

Background

All known ligands of EGF receptor (EGFR) are characterized by the EGF motif and generated from transmembrane precursors. 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. 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. Many peptide ligands of ErbB receptors have been identified, including epidermal growth factor (EGF), heparin-binding EGF-like growth factor (HB-EGF), TGF-␣, amphiregulin, epiregulin, ␤-cellulin, and neuregulin 1– 4 All of these ligands contain one or more of the conserved EGF motif (CX7CX4 –5CX10 –13CXCX8GXRC, where X represents any amino acid) [7, 8], but they differ in receptor specificity [9]. PEPD is a new EGFR ligand and presents a novel mechanism by which EGFR is activated

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DISCUSSION