Chemistry Reference
In-Depth Information
Figure 23.6
CD22 - dependent BCR endocytosis in ST6Gal - I KO mice.
on neighboring CD22 ligands (please see Chapter 27.6 for CD22 and siglecs). CD22
is predominantly associated with clathrin-coated pits in resting B cells, whereas the
BCR is excluded from the clathrin domains. In ST6Gal-I KO mice, CD22 colocalizes
with the BCR in fused raft-clathrin domains due to the dissociation of endogenous
ligand. Consequently, the BCR is downregulated by the clathrin- mediated endocy-
tosis (please see Table 27.4 for phenotype of CD22 KO mice).
1,6 - fucosylation of its
innermost GlcNAc residue (Figure 23.5). This fucosylation is catalyzed by FucT-
VIII (please see Chapters 2.7 and 6.7 and Table 25.2 for further information).
Knockout of FucT-VIII is semilethal during the neonatal period [2]. The surviving
mice eventually show emphysema-like degeneration in the lung tissue. The abnor-
mal production of matrix metalloproteinases (MMP ) - 1, - 12 and - 13 has been
implicated in the induction of emphysema. Signaling through transforming
growth factor ( TGF ) -
Another example of terminal decoration of
N
- glycan is
α
1,6 - fucosylated proteins, negatively
regulates the MMP expression. This is a key factor in regulation of extracellular
matrix ( ECM ) proteins (Figure 23.7). Signaling through the TGF-
β
receptors, which are
α
1 receptor is
downregulated in FucT-VIII null mice as the ligand affi nity to the receptor is less
potent. Therefore, MMPs are highly expressed and consequently the degradation
overwhelmed the synthesis of ECM, which causes emphysema in the mutant
mice. Furthermore, the generation of FucT-VIII KO mice has revealed that
β
1,6 -
fucosylation of
N
-glycans attached to the epidermal growth factor (EGF ) receptor
is required for the binding of EGF. The EGF-induced phosphorylation of the EGF
receptor and subsequent signal transduction are suppressed in the embryonic
fi broblasts established from FucT-VIII KO mice. These results indicate that the
TGF -
α
1 and EGF receptors are functional target proteins for FucT-VIII. These
fi ndings show that it is possible to link a terminal structure of glycans with a spe-
cifi c biological process.
The same is true for glycolipids and proteoglycans. The inactivation of GlcCer
synthase, which acts most upstream in the biosynthetic pathway of glycosphingo-
lipid (please see also Figures 10.2 and 30.3), results in the disappearance of all the
distal structures, even though downstream enzymes are active (shaded area in
Figure 23.8a; please see also Chapters 10.7 and 30.3) [4]. The phenotype of GlcCer
β
