Abstract:Background: Integrin ␣21 is a platelet collagen receptor. Results: Novel sulfonamide derivatives are conformation-selective inhibitors of ␣21, especially when tested under shear stress conditions. Only inhibitors that block non-activated integrins inhibit platelet binding to collagen. Conclusion: Non-activated ␣21 integrin plays an important role in platelet binding to collagen. Significance: We propose an alternative model for ␣21 activation during thrombosis.
“…Our results suggest that the α1 and α2 CT may actually inhibit formation of α1β1 and α2β1 TM/CT heterodimers, at least in bicelles. The stark contrast between the collagen α1β1 and α2β1 integrins and the fibronectin α5β1 integrin suggests that the role of TM/CT domain heterodimerization in regulating integrin function may vary considerably among different β1 integrins, as previously proposed (Nissinen et al, 2012; Abair et al, 2008b; Bazzoni et al, 1998; Pepinsky et al, 2002; Bodeau et al, 2001). …”
Section: Discussionmentioning
confidence: 76%
“…Moreover, contrary to the canonical model, ligand (i.e. collagen) binding to the integrins α1β1 and α2β1 has been reported to occur in the absence of integrin activation (Abair et al, 2008a; Nissinen et al, 2012). Thus, our understanding of the role of the TM interactions between α and β1 integrin subunits in regulating integrin activation and function remains incomplete.10.7554/eLife.18633.003Figure 1.The β1-K752E mutation decreases collecting duct cell adhesion to collagens.( A ) The sequences of the β1 and β3 TM/CTs are annotated.…”
Integrins are transmembrane receptors composed of α and β subunits. Although most integrins contain β1, canonical activation mechanisms are based on studies of the platelet integrin, αIIbβ3. Its inactive conformation is characterized by the association of the αIIb transmembrane and cytosolic domain (TM/CT) with a tilted β3 TM/CT that leads to activation when disrupted. We show significant structural differences between β1 and β3 TM/CT in bicelles. Moreover, the ‘snorkeling’ lysine at the TM/CT interface of β subunits, previously proposed to regulate αIIbβ3 activation by ion pairing with nearby lipids, plays opposite roles in β1 and β3 integrin function and in neither case is responsible for TM tilt. A range of affinities from almost no interaction to the relatively high avidity that characterizes αIIbβ3 is seen between various α subunits and β1 TM/CTs. The αIIbβ3-based canonical model for the roles of the TM/CT in integrin activation and function clearly does not extend to all mammalian integrins.DOI:
http://dx.doi.org/10.7554/eLife.18633.001
“…Our results suggest that the α1 and α2 CT may actually inhibit formation of α1β1 and α2β1 TM/CT heterodimers, at least in bicelles. The stark contrast between the collagen α1β1 and α2β1 integrins and the fibronectin α5β1 integrin suggests that the role of TM/CT domain heterodimerization in regulating integrin function may vary considerably among different β1 integrins, as previously proposed (Nissinen et al, 2012; Abair et al, 2008b; Bazzoni et al, 1998; Pepinsky et al, 2002; Bodeau et al, 2001). …”
Section: Discussionmentioning
confidence: 76%
“…Moreover, contrary to the canonical model, ligand (i.e. collagen) binding to the integrins α1β1 and α2β1 has been reported to occur in the absence of integrin activation (Abair et al, 2008a; Nissinen et al, 2012). Thus, our understanding of the role of the TM interactions between α and β1 integrin subunits in regulating integrin activation and function remains incomplete.10.7554/eLife.18633.003Figure 1.The β1-K752E mutation decreases collecting duct cell adhesion to collagens.( A ) The sequences of the β1 and β3 TM/CTs are annotated.…”
Integrins are transmembrane receptors composed of α and β subunits. Although most integrins contain β1, canonical activation mechanisms are based on studies of the platelet integrin, αIIbβ3. Its inactive conformation is characterized by the association of the αIIb transmembrane and cytosolic domain (TM/CT) with a tilted β3 TM/CT that leads to activation when disrupted. We show significant structural differences between β1 and β3 TM/CT in bicelles. Moreover, the ‘snorkeling’ lysine at the TM/CT interface of β subunits, previously proposed to regulate αIIbβ3 activation by ion pairing with nearby lipids, plays opposite roles in β1 and β3 integrin function and in neither case is responsible for TM tilt. A range of affinities from almost no interaction to the relatively high avidity that characterizes αIIbβ3 is seen between various α subunits and β1 TM/CTs. The αIIbβ3-based canonical model for the roles of the TM/CT in integrin activation and function clearly does not extend to all mammalian integrins.DOI:
http://dx.doi.org/10.7554/eLife.18633.001
“…Unlike what is the case for fibronectin matrices where the cell-binding site is exposed when fibronectin is coated to a stiff surface, the cell-binding site appears to be available to cells without any need for conformational change of the collagen (Seong et al, 2013). It is interesting to note in this context that binding of α2β1 to GFOGER-like motifs of collagen I can occur without the need for inside-out signaling (Nissinen et al, 2012;Siljander et al, 2004) (Box 1). Analyses of signaling pathways that are activated in fibroblasts within 3D collagen matrices have demonstrated α2β1-dependent activation of p38α MAP kinase (MAPK14) signaling and stimulatory effects on collagen synthesis (Ivaska et al, 1999;Ravanti et al, 1999).…”
There was an error published in J. Cell Sci. 129, 653-664.In Fig. 2A, the fibroblasts were incorrectly labelled. The correct annotation should have been α11 −/− fibroblast (left) and α11 +/+ fibroblast (right). The correct Fig. 2 is shown below. We apologise to the readers for any confusion that this error might have caused.
Journal of Cell Science
COMMENTARYThe integrin-collagen connection -a glue for tissue repair?Cedric Zeltz and Donald Gullberg*
ABSTRACTThe α1β1, α2β1, α10β1 and α11β1 integrins constitute a subset of the integrin family with affinity for GFOGER-like sequences in collagens.Integrins α1β1 and α2β1 were originally identified on a subset of activated T-cells, and have since been found to be expressed on a number of cell types including platelets (α2β1), vascular cells (α1β1, α2β1), epithelial cells (α1β1, α2β1) and fibroblasts (α1β1, α2β1).Integrin α10β1 shows a distribution that is restricted to mesenchymal stem cells and chondrocytes, whereas integrin α11β1 appears restricted to mesenchymal stem cells and subsets of fibroblasts. The bulk of the current literature suggests that collagen-binding integrins only have a limited role in adult connective tissue homeostasis, partly due to a limited availability of cell-binding sites in the mature fibrillar collagen matrices. However, some recent data suggest that, instead, they are more crucial for dynamic connective tissue remodeling events -such as wound healing -where they might act specifically to remodel and restore the tissue architecture. This Commentary discusses the recent development in the field of collagen-binding integrins, their roles in physiological and pathological settings with special emphasis on wound healing, fibrosis and tumor-stroma interactions, and include a discussion of the most recently identified newcomers to this subfamilyintegrins α10β1 and α11β1.
“…4). As an alternative strategy to inhibit integrin-lumican binding, PBMC were incubated with the α2 integrin small molecule inhibitor BTT 3033 (58). At 500 nM, BTT3033 did not significantly regulate fibrocyte differentiation in the presence or absence of decorin, but did significantly inhibit lumican-induced fibrocyte differentiation (Fig.…”
In healing wounds and fibrotic lesions, fibroblasts and monocyte-derived fibroblast-like cells called fibrocytes help to form scar tissue. Although fibrocytes promote collagen production by fibroblasts, little is known about signaling from fibroblasts to fibrocytes. In this report, we show that fibroblasts stimulated with the fibrocyte-secreted inflammatory signal tumor necrosis factor-α secrete the small leucine-rich proteoglycan lumican, and that lumican, but not the related proteoglycan decorin, promotes human fibrocyte differentiation. Lumican competes with the serum fibrocyte differentiation inhibitor serum amyloid P, but dominates over the fibroblast-secreted fibrocyte inhibitor Slit2. Lumican acts directly on monocytes, and unlike other factors that affect fibrocyte differentiation, lumican has no detectable effect on macrophage differentiation or polarization. α2β1, αMβ2, and αXβ2 integrins are needed for lumican-induced fibrocyte differentiation. In lung tissue from pulmonary fibrosis patients with relatively normal lung function, lumican is present at low levels throughout the tissue, whereas patients with advanced disease have pronounced lumican expression in the fibrotic lesions. These data may explain why fibrocytes are increased in fibrotic tissues, suggest that the levels of lumican in tissues may have a significant effect on the decision of monocytes to differentiate into fibrocytes, and indicate that modulating lumican signaling may be useful as a therapeutic for fibrosis.
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