Elsevier

Matrix Biology

Volume 26, Issue 3, April 2007, Pages 146-155
Matrix Biology

Mini review
Mammalian collagen receptors

https://doi.org/10.1016/j.matbio.2006.10.007Get rights and content

Abstract

Collagen-rich extracellular matrices are abundant and ubiquitous in the mammalian body. Collagens are not only essential for the mechanical stability of tissues, but are also intimately involved in controlling cell behaviour. The hallmark of collagens is a triple helix made up of polypeptide chains containing glycine-X-Y repeats. A structurally and functionally diverse group of cell surface receptors mediates the recognition of triple-helical collagen: integrins, discoidin domain receptors, glycoprotein VI, leukocyte-associated IG-like receptor-1, and members of the mannose receptor family. In this review, we discuss the structure and function of these receptors, focussing on the principles involved in collagen recognition.

Introduction

Collagens are the most abundant proteins in mammals. Collagen-rich extracellular matrices are not only critically important for the biomechanical properties of tissues, but are also intimately involved in cell adhesion and migration during growth, differentiation, morphogenesis and wound healing. In humans, numerous diseases are caused by mutations in collagen genes, and cell–collagen interactions are perturbed in many other pathological situations (for a recent review, see Myllyharju and Kivirikko, 2004).

All collagens consist of three polypeptide chains, termed α chains, that are characterised by repeating glycine-X-Y sequences. Position X often is occupied by proline and position Y by 4-hydroxyproline (O). The three α chains (which can be identical or different, depending on the collagen type) form a right-handed triple helix, resembling a stiff cable. Glycine is required at every third position to allow the close packing of α chains within the triple helix. Hydroxyproline is required for triple helix stability, but the molecular mechanisms involved in stabilisation are subtle and not completely understood (Vitagliano et al., 2001, Brodsky and Persikov, 2005).

The human genome contains at least 43 distinct collagen α chains that are assembled into 28 collagen types (Myllyharju and Kivirikko, 2004, Veit et al., 2006). In addition, there are more than 20 proteins with collagen-like domains that are not considered collagens, because they do not participate in the formation of supramolecular assemblies. This distinction is not always clear-cut, however. The transmembrane collagens (types XIII, XVII, XXIII and XXV) have yet to be shown to form assemblies, and there may be little to distinguish them from the scavenger receptors, which have a collagenous stalk region but are not included in the collagen family (Myllyharju and Kivirikko, 2004).

All collagen α chains contain non-collagenous domains. In the fibril-forming collagens (types I–III, V, XI, XXIV and XXVII), these domains are proteolytically removed once the triple helix has formed, allowing the lateral association of triple helices into fibrils (Canty and Kadler, 2005). In these fibrils, which account for most of the collagen mass in mammalian bodies, the constituent triple helices are precisely staggered, leading to the banded appearance of collagen fibrils in electron micrographs (Wess, 2005). Non-fibrillar collagens can either associate with collagen fibrils or form supramolecular assemblies themselves. The major basement membrane collagen (type IV), for instance, self-associates to form an extended meshwork, in which key interactions are mediated by the C-terminal non-collagenous (NC1) domains (Timpl and Brown, 1996).

Cells encounter collagen in a number of different ways. Cells may stably adhere to collagen in tissues and thus receive survival signals (e.g. dermal fibroblasts), migrate through the collagen-rich stroma as part of a normal morphogenic process (e.g. mammary gland branching) or in disease (e.g. tumour metastasis), or interact with collagen as a result of injury (e.g. hemostasis). Remodelling of collagen-rich matrices, which occurs widely in both normal and pathological processes, generates collagen fragments whose activities can differ from those of the parent collagen (for reviews, see Ortega and Werb, 2002, Grant and Kalluri, 2005). Given these diverse situations, it is not surprising that mammalian cells use a wide spectrum of proteins and mechanisms to recognise collagen or collagen fragments. For the purpose of this review, we arbitrarily define a collagen receptor as a transmembrane protein that interacts directly with the collagen triple helix (Table 1). A number of collagens have been shown to contain heparin-binding sites within their triple-helical regions (e.g. Sweeney et al., 1998, Delacoux et al., 2000, Vaughan-Thomas et al., 2001) and thus have the potential to interact with cell surface heparan sulphate proteoglycans; these interactions are not further discussed here. In the interest of space, we also exclude from this review: cell–collagen interactions mediated by a third protein; receptors recognising the non-collagenous domains of collagens, especially those transducing the anti-angiogenic effects of proteolytic collagen fragments (Grant and Kalluri, 2005); non-collagen ligands of the receptors discussed in this review; and collagen recognition by bacterial receptors (Zong et al., 2005).

Section snippets

Integrins

Integrins are the major mammalian receptors for cell adhesion to extracellular matrix (for review, see Hynes, 2002). Eight β and 18 α subunits combine to form at least 24 distinct integrins. Both subunits have a large modular extracellular domain, followed by a single transmembrane helix and (with the exception of β4) a short cytoplasmic domain that mediates interactions with the cytoskeleton. Extracellular ligands bind to the integrin head piece, which consists of a seven-bladed β-propeller

Discoidin domain receptors

The discoidin domain receptors, DDR1 and DDR2, constitute a subfamily of receptor tyrosine kinases (RTKs) that function as collagen receptors independent of β1 integrins (Shrivastava et al., 1997, Vogel et al., 1997, Vogel et al., 2000). The DDRs are unique among RTKs in being activated by an extracellular matrix component (typical RTKs are activated by growth factors). Both DDRs are widely expressed during development and in adult tissues (for review, see Vogel et al., 2006). DDR1 is mostly

Glycoprotein VI

Glycoprotein VI (GPVI) is a collagen receptor on platelets that plays a central role in the formation of a hemostatic plug at sites of vascular injury (for reviews, see Ruggeri, 2002, Nieswandt and Watson, 2003, Farndale et al., 2004, Kahn, 2004). The initial contact between platelets and exposed endothelial collagen is made by the platelet complex glycoprotein Ib–V–IX and collagen-bound von Willebrand factor. This interaction is essential at high shear rates, but is not sufficient to result in

Leukocyte-associated IG-like receptor-1

Leukocyte-associated IG-like receptor-1 (LAIR-1) delivers inhibitory signals to various cells of the immune system (Meyaard et al., 1997). LAIR-1 has a relatively simple structure, consisting of a single IG domain, a transmembrane helix and a short cytoplasmic domain containing two immunoreceptor tyrosine-based inhibitory motifs (ITIMs) (Fig. 1A). Until recently the ligand of LAIR-1 was unknown, but expected to be a transmembrane protein by analogy to other ITIM-containing receptors. Expression

Mannose receptor family

The mannose receptor family comprises four members, which have diverse biological functions, but share a common domain architecture: mannose receptor (MR), the M-type phospholipase A2 receptor (PLA2R), DEC-205, and Endo180 (for review, see East and Isacke, 2002). The extracellular domains of these proteins consist of an N-terminal cysteine-rich (CR) domain, a single fibronectin type II (F2) domain, and eight (ten in DEC-205) C-type lectin-like domains (CTLDs), most of which lack sugar-binding

Concluding remarks

In terms of molecular recognition by cellular receptors, the collagens pose several unique challenges. Due to the repeating nature and high imino acid content of collagen triple helices, the scope for specific interactions is more limited than in a globular protein. Moreover, biological function may demand the specific discrimination of fibrillar collagen, isolated triple helices, and denatured collagen (gelatin). Despite these constraints, some mammalian collagen receptors have achieved a

Acknowledgments

We thank Andrew Herr (University of Cincinnati, Ohio, USA) for preparing Fig. 1C. E.H. is funded by a Wellcome Senior Research Fellowship in Basic Biomedical Science.

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      Inhibition of DDR1 and DDR2 by transient siRNA transfection resulted in highly efficient downregulation (Fig. S7A), and siRNA-mediated inhibition of DDR1 reduced adhesion to 57.4% in PANC-1 cells and to 65.2% in SU8686 cells, as determined in an adhesion assay (Fig. 4A). Inhibition of another major collagen receptor [16], β1 integrin (ITGB1), by blocking antibodies reduced the adhesion of PANC-1 cells to 37.3% and of SU86869 cells to 37.4%, whereas the IgG control or blocking of ITGB2, 3, and 4 showed no significant effect. Inhibition of both DDR1 and ITGB1 together reduced the adhesion synergistically, with 16.3% in PANC-1 cells and 3.9% in SU8686 cells.

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