Biology Reference
In-Depth Information
degree of redundancy itself), and recruitment and homing of leukocytes. Could
redundancy explain the overall lack of developmental phenotypes among MMP
null mice? This possibility is suggested by the in vitro observations that multiple
MMPs can cleave the same substrate. For example, at least nine different MMPs
can cleave or degrade fibronectin in vitro. The efficacy, however, with which these
MMPs act on fibronectin in vitro differs among enzymes. If the principal MMP that
cleaves fibronectin in vivo is deleted (and it is not yet clear if fibronectin turnover is
solely the responsibility of an MMP), it is possible that another MMP may degrade
fibronectin but at a slower rate. In a wild-type animal, this lower affinity MMP
would likely not interact with fibronectin, as fibronectin would have already been
bound and processed by the higher affinity MMP; however, in the knockout mouse,
the substrate is suddenly made available, and, as observed in vitro, the lower affinity
MMP subsequently cleaves fibronectin providing redundancy for the system and
leading to a lack of identifiable phenotypes as reduced processing of a substrate
may not be manifest by an overt phenotype. Recently, neutrophil elastase, a serine
proteinase, was suggested to serve a redundant function with MMP9 in facilitating
neutrophil efflux (Kolaczkowska et al.
2008
), but other than this report, evidence
for redundancy among MMP function is lacking.
1.4 Some MMPs Do Act on ECM
1.4.1 Collagen
Elsewhere in this volume, the role of MMPs in degradation of type I collagen
(Chap. 5) and elastin (Chap. 9) is discussed in detail. Metallocollagenases cleave
the triple helix of fibrillar collagen types I, II, and III and possibly others. Although
three human MMPs are called collagenases (MMP1, MMP8, and MMP13), several
other MMPs, especially MMP14 and MMP16 (two of membrane type MMPs), have
been demonstrated to function as physiologic collagenases in vivo (Chun et al.
2004
; Holmbeck et al.
1999
; Holmbeck et al.
2004
; Hotary et al.
2003
; Sabeh et al.
2009
; Shi et al.
2008
). Like the classic collagenases, MMP14 cleaves native type I
collagen at a single locus (Gly
775
-Ile
776
1 chain; Gly
775
-Leu
776
2),
which is located about 3/4 the distance from the N-terminus of the collagen
molecule. At physiologic temperature (37
C), the 3/4- and 1/4-length fragments
of collagenase digestion denature spontaneously into randomly coiled gelatin pep-
tides and can be further attacked by a variety of enzymes, including other MMPs,
such as MMP2 and MMP9, or, in the case of MMP13 and the MT-MMPs, by the
collagenase itself. Furthermore, by being a transmembrane protein, MMP14, as
well as the other membrane-type MMPs, is in an advantageous position to affect
cell movement, and its role in promoting migration and invasion of various cell
types has been reviewed in detail (Seiki
2002
).
in the
in
a
a
