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Mol. Hum. Reprod. Advance Access published online on April 3, 2009
Molecular Human Reproduction, doi:10.1093/molehr/gap029
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© The Author 2009. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Protein processing by the placental protease, cathepsin P

M. Hassanein1,2,3, A. Sri Bojja1,2, L. Glazewski1, G. Lu1 and R. W. Mason1,4

1Department of Biomedical Research, Alfred I duPont Hospital for Children, 1600 Rockland Road, Wilmington, Delaware 19803, USA 2Department of Biological Sciences, University of Delaware, Newark, Delaware 19716, USA

4 Corresponding author: rmason{at}nemours.org

Cathepsin P is a member of a family of placentally expressed cathepsins (PECs). The closest human homolog of cathepsin P is cathepsin L, a broad specificity enzyme that has functions in many tissues in addition to placenta. The gene duplications that gave rise to the PECs provide a rare opportunity to define proteolytic functions in placenta, a transient organ unique to mammals. Peptidyl substrate and inhibitor libraries have shown that cathepsin P has evolved an unusually restricted preference for substrates containing hydrophobic amino acids. Proteomic techniques were used to probe for substrates of this enzyme. Recombinant cathepsin P was incubated with rat choriocarcinoma (Rcho-1) cell proteins to identify substrates using 2-dimensional difference gel electrophoresis. Substrate proteins were excised from gels and characterized by trypsin digestion and MALDI MS/MS. Two endoplasmic reticulum proteins, gp96 and calreticulin, emerged as potential substrates, and Western blotting showed that these proteins are processed by cathepsin P from their C-terminus, removing the KDEL endoplasmic reticulum retention signal. Immunohistochemistry showed that a portion of cathepsin P co-localizes with calreticulin in Rcho-1 cells. Extracellular calreticulin induces differentiation of Rcho-1 cells, indicating a potential role of cathepsin P in processing and secretion of calreticulin during differentiation of trophoblast giant cells.

Key Words: placenta/cathepsin/proteolysis/processing

3 Current address: Dept. Cancer Biology, PRB447, Vanderbilt University Medical Center, 2220 Pierce Avenue, Nashville, TN 37232.

Submitted on November 21, 2008; resubmitted on March 18, 2009; accepted on April 1, 2009.


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