Biology Reference
In-Depth Information
interstitial pH was closer to neutral. In a quite clever and simple experiment, Gross
and Lapiere reasoned that a collagenase had to be involved in the regressing tadpole
tail where bone, cartilage, tendon, vascular, and dermal fibrillar collagen stores are
being rapidly resorbed. Indeed, they discovered and purified a metallocollagenase
that functions at neutral pH. (Although the first MMP discovered, the
Xenopus
collagenase that Gross and Lapiere isolated, was likely what is now called MMP18,
or collagenase-4, for which a mammalian homologue has not been found.) Follow-
ing this lead, essentially all MMPs isolated so far have been shown to be capable of
degrading various protein components of the ECM.
As we discuss, there are actually very little data that directly support the
contentions that MMPs are the main enzymes that degrade the ECM and that
breakdown of ECM is the main function of MMPs. In numerous studies conducted
over the last 13 years with mice lacking specific MMPs, the first MMP knockout
paper was published in 1997 (Wilson et al.
1997
); the data indicate quite convinc-
ingly that these proteinases act on a variety of extracellular proteins, such as
cytokines, chemokines, antimicrobial peptides, and yes ECM proteins too. Conse-
quently, MMP carry out important effector roles in a variety of biologic and disease
processes, with possibly inflammation and immunity being the most common
(Parks et al.
2004
). The importance of the findings generated in MMP null mice
cannot be understated. Understanding what an MMP actually does was not achiev-
able until the consequence of enzyme depletion could be studied in genetically
modified mice. In the following sections, we discuss different criteria, expression
patterns, pericellular location, substrate verification, and established in vivo obser-
vations that are important in understanding and uncovering the functions of MMPs.
1.3.1 Where Do MMPs Function?
An important and simple concept is that MMPs are secreted and anchored to the cell
surface, thereby confining their catalytic activity to membrane proteins or proteins
within the secretory pathway or nearby extracellular space. About 10% of our
genome encodes for proteins with a signal peptide (Clark et al.
2003
), leading to an
extensive array of potential MMP substrates. Thus, it is not surprising that MMPs
evolved to function in a variety of physiologic and disease processes (Cauwe et al.
2007
; McCawley and Matrisian
2001
; Parks et al.
2004
; Stamenkovic
2003
).
A clear division among MMPs, and one that impacts our thinking on function, is
between MMPs with a transmembrane domain (the MT-MMPs) and those without.
MMPs without a transmembrane domain are often called “soluble MMPs,” but this
label is a bit misleading. Modeling and biochemical studies of granular serine
proteinases released by neutrophils demonstrate that proteinases rapidly lose effec-
tive catalytic ability as they diffuse from the cell surface (Campbell et al.
1999
). In
contrast, at the cell surface, enzymes (and other proteins) can be oligomerized into
locally high concentrations. As we have discussed in detail elsewhere (Ra and Parks
2007
), we propose that “soluble” MMPs are anchored to the cell surface by an
