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mice have been generated and show no obvious abnormalities, although no specific
studies of their collagen uptake have been reported (Hanasaki et al. 1997 ).
3.3.2
Integrin-Dependent Pathways
Integrins, heterodimeric membrane proteins involved in cell adhesion and signal-
ing, have been well characterized as the “classical” collagen-binding proteins on
cell surfaces [reviewed in Leitinger and Hohenester ( 2007 )] with
b
1-integrins,
notably
1, being dominant binding components. Whereas their role in collagen
adhesion is well established, their function in endocytic events still needs to be fully
elucidated. This is because the role of integrins in this respect is strongly dependent
on the physical state of the collagen ligand and, possibly, on the assay system
employed.
With solubilized collagen, integrins do not seem to be critical for the endocytic
process. Thus, the internalization of this material by newborn mouse fibroblasts
has been shown to be exclusively dependent on uPARAP/Endo180 and is insensi-
tive to blocking of
a
2
b
1-integrins (Engelholm et al. 2003 ). In contrast, the uptake of
b
collagen-coated (1-
m diameter) beads by gingival fibroblasts was markedly
reduced in the presence of a blocking antibody against
m
1 integrin, suggesting
a major role of this integrin, at least in the initial collagen-binding step preceding
this uptake event (Arora et al. 2000 ; Segal et al. 2001 ). In the same system, the
vesicles surrounding the collagen beads after cellular uptake were isolated and
analyzed at various time points. This investigation revealed several characteristics
consistent with a classical phagocytic process, including a maturation of phago-
somes to phagolysosomes. Thus, there was an initial association of the bead
vesicles with
2
a
b
-actin and the actin-binding protein, gelsolin, a subsequent fusion
with particles containing cathepsin B and lysosomal markers and an ultimate
degradation of the collagen material (Arora et al. 2000 ). A functional importance
of gelsolin in this phagocytic process was revealed in a subsequent work, which
also demonstrated its dependence on Rac activation (Arora et al. 2004 ). The
collagen-binding matrix proteoglycan, decorin, may act as a regulator of collagen
phagocytosis through this mechanism because collagen-coated beads that included
decorin displayed reduced cellular binding in the same system as described above
(Bhide et al. 2005 ).
These studies may help to clarify several mechanisms lying behind collagen
phagocytosis by fibroblasts, a phenomenon that has been rigorously demonstrated
by electron microscopy in early work [reviewed in Everts et al. ( 1996 )]. However,
an integrin-mediated collagen uptake in some phagocytic processes does not
exclude a role of the MR receptor family members in the same type of events. In
the above-mentioned study on genetically (MMTV-PymT) induced mammary
tumors in uPARAP/Endo180-deficient mice, electron microscopy revealed an
absence of intracellular vesicles with banded collagen in the tumor-associated
fibroblasts. In the tumor fibroblasts from uPARAP/Endo180-expressing littermates,
b
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