Extracellular matrix and cell signalling: the dynamic cooperation of integrin, proteoglycan and growth factor receptor
- Division of Biomedical Sciences, St George's Medical School, University of London, Cranmer Terrace, London SW17 0RE, UK
1Institute of Integrative Biology, Centre for Glycobiology, University of Liverpool, Crown Street, Liverpool L69 7ZB, UK
- (Correspondence should be addressed to S-H Kim; Email: skim{at}sgul.ac.uk)
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Figure 1
Mechanisms proposed for growth factor signalling regulation by integrins. (A) The repertoire of integrins expressed on a particular cell can specify the signal pathway due to the differential binding affinity of ECM ligands for the integrins. The tissue stiffness and matrix composition can initiate specific signalling pathways regulating cell behaviour. Clustering and activation of the integrins/actin complexes strengthen the focal adhesion interaction and initiate the framework for cell signalling through assembly of adhesomes. (B) Integrins, via their cytoplasmic domain, recruit specific adaptors to the plasma membrane, which regulate the growth factor receptor signalling. For example, β1c integrin recruits Gab1/Shp2 and presents Shp2 to IGF1R, resulting in dephosphorylation of the receptor (Goel et al. 2005). (C) In response to growth factor stimulation, integrins co-localise at focal adhesion with the growth factor receptors and their associated signalling molecules, such as Src and FAK, as well as with cytoskeletal molecules such as paxillin, talin, and vinculin. For example, the α2β1 integrin co-localises with EGFR (Yu et al. 2000), which eventually regulate the activity of the downstream effectors such as ERK, AKT, JNK, and the Rho GTPases. The details of these downstream pathways can be found in other recent reviews (Legate et al. 2009). (D) Integrins can change the rate of growth factor receptor internalisation and degradation. One such example is the interaction of EGFR1 and α5β1 integrin, which is co-ordinately recycled to the plasma membrane, regulating the protein kinase B (PKB) signalling (Caswell et al. 2009). Integrin-mediated cell adhesion can also alter PDGFR rate of degradation via ubiquitination (Baron & Schwartz 2000).
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Figure 2
Different HS structures support different biological activities. (A) Heparan sulphate that has different cell- and tissue-specific structures (denoted schematically by red, yellow and green bars) with binding domains for different growth factors. Here, green represents structures that are capable of binding to both FGF and FGFR, thus supporting ligand-induced dimer formation and consequent signalling in the FGFR complexes. Yellow structures cannot bind to FGF or FGFR, but are capable of binding to PDGF and regulating its activity. Red structures can bind to FGF, but cannot support subsequent binding to FGFR. (B) Heparan sulphate that lacks the required structures (green) cannot support FGF signalling through FGFR, although the presence of other structures (red) still allows it to bind to FGF without supporting its activity. Other structures (yellow) may bind and regulate PDGF, mediating alternative signal pathway.
- © 2011 Society for Endocrinology
