Chemistry Reference
In-Depth Information
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The protein core of syndecans also contributes to their function. That is, the
syndecans have properties beyond the ability to bind and concentrate HS- binding
ligands at the cell surface. Thus, the isolated ectodomain of SDC1 and 4, free of
HS side-chains, promotes the adhesion of human fi broblasts and B-lymphoid
cell lines. Moreover, the cytoplasmic domain of SDC4 may initiate a signal
cascade by formation of a ternary complex which comprises two dimers of
syndecan ectodomains, phosphatidylinositol 4,5-bisphophate and protein kinase
C. This complex acts as a phosphorylate regulator of Rho family GTPases and
actin-associated proteins, and leads to activation of Rho kinases.
•
Syndecans are shed from the cell surface by enzymatic cleavage of the core
protein. The enzyme responsible (sheddase, secretase, convertase) was identifi ed
as a TIMP-3-sensitive MMP. Several pathways (receptor activation, mitogen-
activated protein kinase, c-Jun N-terminal kinase and protein tyrosine kinase)
are involved in triggering the shedding process. Shedding can be accelerated by
exogenous proteases like thrombin and plasmin. The shedding process releases
a soluble fragment corresponding to the ectodomain which can act as a dominant-
negative form competing for binding partners with the membrane-integrated
syndecan. The cleavage sites are located in immediate proximity to the
transmembrane domain. Shed syndecans have been found in serum and in
body fl uids during wound healing and cancer.
Syndecans have the ability to replace each other in functional terms, at least
partially. SDC-1 and SDC-4 null mice (SDC1
− / −
and SDC4
− / −
) exert a normal phe-
notype, they are viable and fertile, and develop well. However, under strain condi-
tions such as injury or in disease models some loss of function becomes
evident - retarded wound healing and reepithelization, defective angiogenesis in
granulation tissue, and atypical binding of leukocytes to vascular endothelium.
11.6.2
Glypicans
Glypicans (GPC) [24] are a family of HSPGs which are anchored to cell mem-
branes by a glycosylphosphatidylinositol (GPI) linkage (for further information on
GPI anchors, see Chapter 9). So far six members (GPC1-6) are known in verte-
brates. The chromosomal location has been established. A schematic structure of
GPC1 is given in Figure 11.8. The glypican protein components anchored in this
manner are called 'glypiated'. The GPI anchor generally consists of a phosphati-
dylinositol phosphoglyceride whose inositol group has been modifi ed by acylation
and an oligosaccharide. A phosphoethanol group present on the terminal mannose
serves as an acceptor site for the protein. Glypican family member are selectively
expressed on different cell types with only GPC1 present in vascular cells. The
proteo-HS of glypican is mainly targeted to apical surfaces and this process is
partially dependent upon the extent of glypiation. In human brain glypican is
accumulated in DIG (detergent-insoluble glycophospholipid)-enriched domains of
cell membranes and regularly colocalizes with A
β
particles in human brain of
