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Volume 270, Number 29, Issue of July 21, pp. 17154-17158, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.

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Extracellular Conversion of Epidermal Growth Factor (EGF) to des-Arg-EGF by Carboxypeptidase M

(Received for publication, March 21, 1995)

From the Departments of Pharmacology and Anesthesiology, Laboratory of Peptide Research, University of Illinois College of Medicine, Chicago, Illinois 60612

Epidermal growth factor (EGF) is a 53-amino-acid mitogenic polypeptide present in a variety of tissues and fluids including kidney, urine, and amniotic fluid. An EGF isoform, des-Arg-EGF, has been identified in urine and is the earliest metabolite generated in target cells upon EGF binding. In this study, purified carboxypeptidase M efficiently released the COOH-terminal arginine residue from EGF with a K = 56 µM, k = 388 min, and k/K = 6.9 µM min. When EGF was incubated with urine or amniotic fluid, des-Arg-EGF was the only metabolite detected. This conversion was blocked by immunoprecipitation with specific antiserum to carboxypeptidase M or by 10 µMDL-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid (a carboxypeptidase M inhibitor), indicating that the major EGF metabolizing enzyme in these fluids is carboxypeptidase M. When incubated on a confluent monolayer of Madin-Darby canine kidney (MDCK) cells, EGF was readily converted to a single metabolite, des-Arg-EGF, by carboxypeptidase M. To investigate one possible functional consequence of this conversion, mitogenic activities of EGF and des-Arg-EGF were tested. Both peptides were equipotent in stimulating [H]thymidine incorporation in MDCK cells at all doses tested. In addition, inhibition of the conversion of EGF to des-Arg-EGF by the carboxypeptidase M inhibitor did not affect the mitogenic potency of EGF. These data indicate that carboxypeptidase M, present in a variety of cells and biological fluids, can convert EGF to des-Arg-EGF. However, in contrast to many other peptide hormones whose activity depends on a final carboxypeptidase processing step, removal of Arg of EGF is not required for its mitogenic activity.

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