Biology Reference
In-Depth Information
clathrin-coated pits. The four members are the (macrophage) mannose receptor
(MR), the uPAR-associated protein (uPARAP/Endo180), the M-type phospholi-
pase A2 receptor (PLA2R), and the dendritic cell receptor DEC-205/gp200-MR6
(in the following designated DEC-205). All of these receptors contain a fibronectin
type II domain, a domain type that is frequently associated with collagen interac-
tions. Binding and internalization of collagen/gelatin have been positively demon-
strated for the first two of these members, as detailed in the following.
3.3.1.1 uPARAP/Endo180
The most well-characterized endocytic collagen receptor is uPARAP/Endo180, also
designated MRC2 or CD280. This receptor is a membrane protein of
M
r
180,000
with an amino acid sequence clearly revealing that it belongs to the MR protein
family (Behrendt et al.
2000
; Sheikh et al.
2000
; Wu et al.
1996
). The molecular
properties of uPARAP/Endo180 have been reviewed recently (Engelholm et al.
2009
). It contains ten extracellular domains, of which only two have an identified
function. These are the fibronectin type II domain, which takes part in collagen/
gelatin recognition (Wienke et al.
2003
) and an active C-type lectin domain recog-
nizing
N
-acetylglucosamine, fucose, and mannose residues (East et al.
2002
). This
lectin domain is the second out of eight sequential lectin-like domains, but appears to
be the only one of these to possess a carbohydrate-binding activity. In addition to the
collagen interactions to be detailed below, uPARAP/Endo180 has been found in a
complex with urokinase and the urokinase receptor (Behrendt et al.
1993
). Various
cellular functions, unrelated to matrix turnover, have been assigned to interactions
between uPARAP/Endo180 and the urokinase system (Sturge et al.
2003
), but they
will not be included in this discussion.
The binding of collagen to uPARAP/Endo180 has been observed on whole cells
(Behrendt et al.
2000
) as well as in a purified system (Madsen et al.
2007
). There is a
binding preference for denatured collagen and for collagen that has been subjected
to specific cleavage by MMPs (Madsen et al.
2007
). uPARAP/Endo180-dependent
cellular internalization of collagen has been observed with all collagen subtypes so
far tested, including the major fibrillar (type I) and sheet-like (type IV) collagens
(Engelholm et al.
2003
; Kjoller et al.
2004
; Wienke et al.
2003
). In fibroblasts
when assayed with solubilized collagen, there is a total dependence of this receptor
for cellular collagen uptake, as shown by a complete lack of collagen internalization
in fibroblasts from uPARAP/Endo180-deficient mice (Engelholm et al.
2003
).
uPARAP/Endo180 also appears to be engaged in collagen uptake in cultured hepatic
stellate cells (Mousavi et al.
2005
), osteoblasts, and chondrocytes (Wagenaar-Miller
et al.
2007
) and, at least in the collagen-binding step, in cultured osteosarcoma and
fibrosarcoma cells (Wienke et al.
2003
).
uPARAP/Endo180 is constitutively internalized from clathrin-coated pits, typi-
cally with an internalization half-life of just a few minutes (East et al.
2002
) and
is recycled from the early endosomal compartment to the plasma membrane