Chemistry Reference
In-Depth Information
it. It has been convincingly demonstrated that tumor cells exhibit altered surface
expression of carbohydrate moieties compared to their normal counterparts. For
instance, surface expression of CD15s is positively correlated with tumor progres-
sion and the capacity to form metastases. In addition, other forms of the Le
histo-blood group family like Le
a
and Le
y
are frequently expressed on human
carcinomas. These oligosaccharide sequences may also serve as selectin ligands,
primarily for CD62E and CD62P, although this has not yet been extensively
studied.
Selectins preferentially bind to carbohydrate structures of the Le blood group
family and have vital functions both in directing leukocytes to sites of infl amma-
tion and in homing of lymphocytes to lymph nodes. We next explain how the
complex group of galectins is involved in diverse immune reactions.
27.5
Galectins
Galectins are an ancient family of lectins that do not contain a transmembrane-
spanning domain like selectins (for fold, please see Figure 13.2). They are soluble
molecules found in the outer environment, on the cell surface in dimeric form,
in the cytoplasm and even in the nucleus. This makes their functional analysis
more diffi cult than of membrane-anchored lectins (see Chapters 15 , 16 and 19 ).
Galectins are defi ned by their affi nity for the
β
- galactoside core; however, they
differ in their affi nity for substituted
- galactosides complex carbohydrate
sequences (see Chapters 13, 19 and 25). A multitude of functions has been
ascribed to galectins (please see Table 19.2 for respective entries). Here, we con-
β
Figure 27.2
Illustration of lectin (galectin) sig-
naling during T cell apoptosis. (Top panel) Bind-
ing of a lectin (L) to a cell surface receptor (R)
induces receptor clustering and initiation of
signaling. Hereby a cellular response is gener-
ated, in this case apoptosis. (Bottom panel)
Galectin-1 homes in on distinct cell-surface gly-
coproteins as receptors, such as CD7, CD43
or CD45. This interaction triggers apoptosis
because the activation of sphingomyelinase
induces increased levels of ceramide. The ensu-
ing activation of the initiator proteases cas-
pase-8 (casp8) and caspase-9 (casp9) and their
effectors caspase-3, -6 or -7 results in the deg-
radation of intracellular proteins. Active cas-
pase-9 is produced from its inactive precursor
by the apoptosis - activating factor - 1 (Apaf - 1)
when cytochrome
c
(cyt c) is available in the
cytosol. This requirement is met by the galec-
tin-dependent upregulated expression of the
pro-apoptotic protein Bax and the downregula-
tion of the anti-apoptotic protein Bcl- 2. Overall,
these two proteins regulate the permeability of
the outer mitochondrial membrane in an antag-
onistic manner. Tilting the balance in favor
of Bax lets cytochrome
c
enter the cytosol. In
addition to protein fragmentation, the effector
caspases also facilitate DNA degradation via
caspase-activated DNases (CAD). Prior to
their nuclear translocation, a caspase-activated
DNase inhibitor is cleaved by the caspases.
Furthermore, galectin-1 operates by a mecha-
nism involving the endonuclease G (EndoG )/
apoptosis - inducing factor ( AIF ) complex, fi rst
released in a Bax-dependent manner from mito-
chondria and thereafter translocated to the
nucleus. The abbreviations used are: ext, extra-
cellular medium; cyt, cytosol; ncl, nucleus; ims,
intermembrane mitochondrial space; mat, mito-
chondrial matrix.
