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Title: Syndecan-4 regulates cell-surface trafficking and biological activity of transglutaminase-2
Author: Scarpellini, A.
Awarding Body: Nottingham Trent University
Current Institution: Nottingham Trent University
Date of Award: 2009
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Transglutaminase-2 (TG2) is a Ca2+-dependent crosslinking enzyme involved in the post-translational modification of proteins via the formation of Nε(γ-glutamyl)lysine isodipeptides. TG2 is externalised in the extracellular matrix (ECM) through an unconventional and not fully understood pathway. Under normal conditions, TG2 modulates cell adhesion, proliferation and tissue repair. Under continuous cell insult higher expression and elevated extracellular trafficking of TG2 contribute to the pathogenesis of tissue scarring. TG2 is known to have affinity for heparin, and in a previous study cell-surface heparan sulphate (HS) has been implicated in extracellular TG2 mediated RGD-independent cell adhesion, a non-enzymatic process independent from the α5β1 integrin-binding to the RGD domain on FN (Verderio et al., 2003). Hence HS proteoglycan (HSPG) could act as cell surface co-receptor for FNbound TG2 or contribute to the regulation of extracellular TG2 activity in cell adhesion and tissue repair. The aims of this study were: 1) to study the role of externalised TG2 in cell adhesion in primary fibroblasts. 2) to investigate the role of HSPG syndecan-4 (Sdc-4), a crucial component of focal adhesions in TG2-mediated cell-adhesion. 3) to characterise the interaction between TG2 and HSPG, in particular Sdc-4, and to investigate how this interaction can influence TG2 biological functions in vitro. 4) to examine the role of Sdc-4 as a regulator of pro-fibrotic TG2 activity in experimental model of kidney fibrosis (UUO). The results obtained have shown that: 1) externalised TG2 plays an important role in mediating early events of cell adhesion in primary fibroblasts. 2) FN-bound TG2 relies on the presence of Sdc-4 for its role in RGD-independent cell adhesion. 3) TG2 has a high affinity for HS (Kd ~ 20 nM) and it is associated with Sdc-4 at the cell surface in primary fibroblasts. 4) TG2 crosslinking activity at the cell surface relies on the presence of the HS chains of Sdc- 4 and other HS proteoglycans. HS-binding does not have a direct role in TG2 activity regulation, but the presence of intact Sdc-4 is essential for TG2 localisation at the cell surface. 5) Sdc-4 is protective against the development of UUO and it regulates the release and activity of the pro-fibrotic factor TG2 in UUO, suggesting a possible co-operative role of TG2 and Sdc-4 in the development of kidney fibrosis. In conclusion, HSPG, and in particular Sdc-4 emerged to have a crucial role in the cellsurface trafficking and regulation of TG2 biological activities both in vitro and in vivo.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available