Biology Reference
In-Depth Information
Specific binding of secreted MMP-9 to the hyaluronan receptor CD44 and the
formation of stable cell surface MMP-9/CD44 complexes provide a mechanism for
CD44-mediated carcinoma and melanoma cell invasion of collagen IV matrices
in vitro and tumor invasion in vivo (Yu and Stamenkovic
1999
) and represent another
example when the proteolytic activity of a secreted MMP is localized to the pericel-
lular environment. On the other hand, CD44 functions as the docking molecule for
MMP substrates, e.g., heparin-binding precursor of EGF processed by MMP-7 (Yu
et al.
2002
) or heparin-bound TGF
processed by MMP-9 (Yu et al.
2002
), or serves
as a direct substrate of MT1-MMP (Seiki
2002
). In addition, MMP-9 can dock on
a
b
1/CD44 complexes on the surface of leukemic cells (Redondo-Munoz et al.
2008
,
2010
) or directly bind to
4
b
b
5(Bjorklundetal.
2004
)and
b
1 integrins on invasive tumor
cells (Radjabi et al.
2008
; Redondo-Munoz et al.
2008
).
The mechanisms that direct secreted MMPs to the cell surface often involve their
corresponding hemopexin (PEX) domains (Piccard et al.
2007
). The schematic
representation of various PEX domains mediating cell surface binding of select
secreted MMPs is depicted in Fig.
7.2
. Thus, complex formation between
1 and
MMP-1 requires the linker and hemopexin (PEX) domains of the proenzyme
(Dumin et al.
2001
). The hemopexin domain is obligatory for complex formation
between MMP-9 and its docking CD44 and
2
a
b
1 integrin molecules (Yu and
Stamenkovic
1999
; Bjorklund et al.
2004
; Redondo-Munoz et al.
2010
). PEX-
mediated binding has also been implicated in the cell surface localization of
MMP-28 in lung carcinoma A549 cells (Illman et al.
2006
), although the cell surface
receptor of MMP-28 was not identified. The involvement of PEX domains of
secreted MMPs during their cell surface binding or during homodimerization
of membrane-type MMPs (Itoh et al.
2006
) may mechanistically link the ability of
PEX to guide MMPs and adapt substrate recognition by MMPs (Cha et al.
2002
;
Mori et al.
2002
; Van den Steen et al.
2006
; Piccard et al.
2007
) with the requirement
of directional matrix proteolysis and remodeling during cell invasion. This notion is
supported by a number of in vitro and in vivo studies where expression of PEX-
mutants or delivery of soluble PEX domains of select MMPs, e.g., MMP-2 (Brooks
et al.
1998
; Pfeifer et al.
2000
), MMP-9 (Roeb et al.
2002
; Burg-Roderfeld et al.
2007
; Mantuano et al.
2008
; Ezhilarasan et al.
2009
), or MT1-MMP (Cao et al.
2004
), effectively suppressed tumor growth and angiogenesis and inhibited cell
migration and matrix invasion by tumor and endothelial cells.
b
7.6 Pericellular Proteolysis and Directional Cell Invasion
Mediated by Specialized Membrane Structures
The main mechanism underlying pericellular proteolysis by MMPs includes their
recruitment to the sites of cell receptor-substrate contacts to provide focalized
degradation of specific ECM molecules (Fig.
7.3
). The focalized matrix proteolysis
occurs at highly specialized cell adhesion-motility structures, including lamellipo-
dia, filopodia, invadopodia, and podosomes, where MMPs act in tight coordination
