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Ectopeptidases in pathophysiology
Christophe Antczak,
1,2
Ingrid De Meester,
1,3
and Brigitte Bauvois
1
*
Summary
Ectopeptidases are transmembrane proteins present in a
wide variety of tissues and cell types. Dysregulated
expression of certain ectopeptidases in human malig-
nancies suggests their value as clinical markers. Ecto-
peptidase interaction with agonistic antibodies or their
inhibitors has revealed that these ectoenzymes are able
to modulate bioactive peptide responses and to influence
growth, apoptosis and differentiation, as well as adhe-
sion and motility, all functions involved in normal and
tumoral processes. There is evidence that ectopeptidase-
mediated signal transduction frequently involves
tyrosine phosphorylation. Combined analyses of gene
organization and regulation of ectopeptidases by various
physiological factors have provided insights into their
structure±function relationships. Understanding the
roles of ectopeptidases in pathophysiology may have
implications in considering them as therapeutic tar-
gets. BioEssays 23:251±260, 2001.
ß 2001 John Wiley & Sons, Inc.
Introduction
Cells communicate with their environment through several
kinds of cell surface receptors including cytokine receptors, cell
adhesion molecules and ectoenzymes. A distinctive feature of
ectoenzymes, represented by nucleotidases,glycohydrolases,
phosphorylases, ADAMs (
a disintegrin and metalloprotease
family), secretases and peptidases, is that they are integral
membrane proteins with an active catalytic site exposed to the
external surface of the membrane.
(1± 3)
This article focuses on
ectopeptidases. Today, around twenty ectopeptidases have
been identified in human cell types and tissues (Fig. 1). They
are anchored in the plasma membrane either with the N
terminus or the C terminus facing extracellularly or through the
glycosyl-phosphatidylinositol moiety (Fig. 1). Ectopeptidases
lead a dual existence as membrane-bound and soluble
isoforms found in body fluids (Fig. 1). Enzyme release is
sometimes associated with pathology as seen in granuloma-
tous inflammation with overproduction of serum angiotensin-
converting enzyme (ACE), or during the course of hepatitis C
characterized by enhanced levels of serum g-glutamyl
transpeptidase (g-GT). The mechanisms for regulating the
shedding of membrane ectopeptidases are unknown except
for ACE which is released by a member of the secretase
family.
(2)
Interestingly, certain surface molecules initially
identified by immunologists and hematologists as
cluster of
differentiation (CD) antigens are identical to well-studied
ectopeptidases i.e. aminopeptidase N (APN), dipeptidyl
peptidase IV (DPPIV), neutral endopeptidase (NEP) and
ACE (Fig. 1). Based on their aminoacid sequences, ectopep-
tidases belong to different families and clans of proteases
indicating their different origin. At present, there is no evidence
for extended sequence homology between all members of
ectopeptidases that could explain their developmental regula-
tion and their functional similarity. The structure and enzymatic
action of most ectopeptidases have been the subject of recent
reviews
(4± 12)
and will not be detailed here. Although almost all
ectopeptidases are widely distributed, their levels of expres-
sion vary considerably during the fetal/postnatal development
stages
(4±13)
and in inflammatory reactions.
(13)
Several inves-
tigations have reported that physiological stimuli regulate
ectopeptidase expression and will be summarized here. An
essential question for clinicians and scientists is whether
ectopeptidases critically contribute to the disease process. We
will describe here salient advances in the molecular genetics of
ectopeptidases, and what is currently known of their biological
activities.
Expression of ectopeptidases in disease
There are many reports of the dysregulated expression of
ectopeptidases in human leukocyte malignancies and they
have been frequently used as diagnostic markers (Table 1;
Fig. 2). NEP, DPPIV and g-GT are overexpressed in several
forms of B leukemias and T/B lymphomas.
(4,6,14,15)
APN and g-
GT are overexpressed in acute and chronic myeloid leuke-
mias
.(16±18)
In contrast, the loss of DPPIV and g-GT from the
surface of lymphocytes is associated with acute and chronic T
lymphocytic leukemic diseases.
(19,20)
Ectopeptidases also
appear to be dysregulated in putative autoimmune diseases
such as multiple sclerosis (21, 22) and rheumatoid arthri-
tis
(23,24)
as well as sarcoidosis
(7)
and HIV infection
(6,25)
(Table 1).
Outside of the hematopoietic system, the expression
pattern of ectopeptidases in solid tumor malignancies has
been extensively reviewed by Nanus and collaborators
(26)
and
BioEssays 23:251±260, ß 2001 John Wiley & Sons, Inc. BioEssays 23.3 251
1
Institut Curie, INSERM 365, Paris, France.
2
Institute Curie, CNRS UMR 176, Paris, France.
3
Department of Pharmaceutical Sciences, University of Antwerp,
Belgium.
Funding agencies: Institut National de la Sante
Â
et de la Recherche
Me
Â
dicale (INSERM); Dr De Meester is a senior research assistant of
the Fund for Scientific Research Flanders.
Correspondence to: Brigitte Bauvois, Unite
Â
365 INSERM, Institut
Curie, 26, rue d'Ulm, 75231 Paris cedex 05, France; E-mail:
brigitte.bauvois@curie.fr
Review articles