Polymerization of Type I and III Collagens Is Dependent On Fibronectin and Enhanced By Integrins α11β1and α2β1

Abstract

We have studied the role of collagen receptors, integrins ␣ 11 ␤ 1 and ␣ 2 ␤ 1 , and fibronectin in collagen polymerization using fibronectin-deficient mouse embryonic fibroblast cell lines. In contrast to the earlier belief that collagen polymerization occurs via self-assembly of collagen molecules we show that a preformed fibronectin matrix is essential for collagen network formation and that collagen-binding integrins strongly enhance this process. Thus, collagen deposition is regulated by the cells, both indirectly through integrin ␣ 5 ␤ 1 -dependent polymerization of fibronectin and directly through collagenbinding integrins.Collagens form a large family of proteins with more than 20 different members described to date (3). The organization of different collagens into various types of fibrils and networks in extracellular matrices (ECM) 1 is of crucial importance for the physical properties of tissues. Type I and III collagens, the predominant proteins in the body, are prototypes for the fibrillar collagen subfamily. Although these collagens are known to serve as a scaffold for numerous associated proteins, proteoglycans, and cells in the ECM, the mechanisms that regulate their own polymerization are poorly understood.As all collagens, types I and III are composed of three ␣ chains that form triple-helical domains. The collagen triplehelices are assembled intracellularly in a process dependent on ascorbic acid as a cofactor for hydroxylation of selected prolines and lysines (4). In addition to the triple-helical region, procollagen molecules of type I and III collagens contain a propeptide in both the N-and C-terminal ends as well as the so-called telopeptides. In connection with secretion of the monomers into the extracellular space, the propeptides are usually removed by proteolytic cleavage. Removal of C-terminal propeptides is a prerequisite for the fibrillogenesis. For instance the ␣1(I) collagen chain, where the C-propeptide cleavage site was mutated, could not be incorporated into the fibrillar cross-linked collagen matrix (5). The fate of the N-terminal propeptides varies between the different collagens. Although it is efficiently removed from type I collagen, the N-terminal propeptide of type III collagen appears to be a normal constituent of the interstitial ECM (6 -8). The exact way by which type III procollagen is processed, the size of the pool of the N-propeptide that is not removed in different tissues, and its function(s) are currently not known. In contrast to the propeptides, the C-and N-terminal telopeptides of secreted mature collagen molecules are fully retained. The telopeptides, as well as the N-terminal propeptide of type III procollagen, serve as good antigenic markers due to their unique collagen type-specific sequences.Type I and III collagens isolated from tissues can polymerize in vitro, and therefore the fibrillogenesis in tissues has been thought to occur in a similar way via self-assembly guided by precise interactions between collagen molecules followed by organization of ...

Syndecan-1 in Breast Cancer Stroma Fibroblasts Regulates Extracellular Matrix Fiber Organization and Carcinoma Cell Motility

“…An intact FN matrix is essential for the formation and stability of a mature collagen-containing ECM. 39,40 Therefore, the regulation of FN fibril assembly may hold the key to understanding matrix organization. Fibronectin fibrillogenesis is a complex cell-mediated process that involves FN binding to cell surface receptors, FN-FN self-association, and interaction with the actin cytoskeleton.…”

Spatiotemporal protein distribution of TGF‐βs, their receptors, and extracellular matrix molecules during embryonic tendon development

“…Decorin and fibronectin have both been shown to associate with collagens, and play critical roles in regulating fibrillogenesis of collagen types I and III (Engvall et al, 1978;Kleinman et al, 1981;Fleischmajer and Timpl, 1984;Speranza et al, 1987;Birk et al, 1995;Danielson et al, 1997;Graham et al, 2000;Velling et al, 2002). In connective tissues, including blood vessels and skin, collagen type III colocalizes with collagen type I within the same fibril, presumably to regulate the size of collagen type I fibrils (Fleischmajer et al, 1988(Fleischmajer et al, , 1990.…”

“…Binding of collagen fibrils by fibronectin regulates fibrillogenesis in vitro, presumably due to the high affinity of fibronectin to collagen type III, which competes with other collagen molecules to result in inhibited fibrillogenesis (Speranza et al, 1987). On the other hand, a recent study has provided evidence that an existing fibronectin matrix is essential for collagen deposition and network formation (Velling et al, 2002). Whereas the specific function of fibronectin during tendon development has yet to be elucidated, our observations, taken together with those from previous studies, strongly suggest that this particular matrix molecule plays an important role in fibrillogenesis during tendon development.…”

New insights into elastic fiber assembly

“…A movie with all of the frames from the live imaging study is included in the online Supplemental Material (Movie B{MOVB}). Fibronectin is not generally considered an elastic fiber protein, but an initial fibronectin scaffold is necessary for collagen type I and type III matrix assembly in vitro (Velling et al, 2002) and may be associated with elastic fiber assembly, at least in vitro. LOX binds to fibronectin with a similar affinity to tropoelastin, but does not act on fibronectin enzymatically.…”