Chemistry Reference
In-Depth Information
receptors may no longer maintain their regular activity, as though being exposed
to a blocking antibody. In other words, a deviation in glycan structure from the
normal phenotype accounts for functional consequences ranging from modulat-
ing binding activity of a ligand to growth retardation of mice (Table 25.2 ). Indeed,
the examples given in Table 25.2 from the study of models underscore that tumor-
associated changes in glycan display bring about changes in cell behavior. Without
requiring a tumor-specifi c event, shifts in glycosylation are thus not merely phe-
nomenological aberrations (for further information on the relationship between
glycosylation and disease
in vivo
, see Chapters 22 and 23; on therapeutic approaches
by interfering with glycosylation, see Chapter 28.1). Obviously, glycan chains can
act as molecular switches on protein activities in a glycoprotein by virtue of adopt-
ing distinct conformations [6]. Even seemingly subtle modifi cations, for example
presence of core fucosylation conspicuously distant from branch-end sugars in
extended antennae, will be effective (for details, please see Table 25.2 ), and there
is a second functional dimension alluded to above. In fact, the same sensitivity of
Table 25.2
Examples for the impact of structural changes in the glycan part of cell surface glycoproteins on
their functionality.
Protein
Experimental system
Altered glycosylation
Functional consequence
EGFR
Overexpression of GnT - III
(Mgat3) in transfected human
cervical adenocarcinoma He-
LaS3 cells
Increased level of bisecting
GlcNAc
Reduced EGF binding
(low - affi nity sites), in-
creased internalization and
ERK phosphorylation
EGFR
Downregulation of GnT - V
(Mgat5) by small interfering
RNA in metastatic and inva-
sive human breast carcinoma
MDA - MB231 cells and breast
carcinoma cells from GnT-V
(Mgat5) null mice
Reduced level of
N
- linked
Suppression of FAK sig-
naling despite unaltered
EGF binding, increased re-
ceptor internalization, re-
duced signaling, tumor cell
invasiveness and growth
β
1,6 - branching
EGFR
FucT - VIII overexpression in
transfected human embryonic
kidney HEK293 cells
Enhanced core fucosylation
Enhanced EGF - dependent
cell growth and sensitivity
to gefi tinib (an EGFR inhi-
bitor)
EGFR
Stable FucT - VIII knock - down
by short hairpin RNA in
human embryonic kidney
HEK293 cells and human
lung cancer A549 cells
Reduced core fucosylation
Decreased EGF - dependent
cell growth and sensitivity
to gefi tinib
continued
