ReviewMatricellular proteins: extracellular modulators of cell function
Introduction
In vertebrates, the extracellular matrix (ECM) determines the physical properties of tissues, as well as many of the characteristics of the cells within them. In some cases, the same constituent matrix protein can perform these different functions. Thus, collagen-I, the prototypic structural protein in bone, tendon and ligament, also serves as an adhesive protein, and monomeric and polymeric forms of the protein affect cells differently [1]. It is nevertheless useful for heuristic purposes to identify different functional compartments within the ECM, and to categorize the proteins within them.
The pericellular matrix refers to a subcompartment of the ECM, adjacent to the cell, which contains growth factors, cytokines, proteases, and other bioactive molecules that interact with the cell surface. These proteins, together with proteoglycans, polymeric collagen and fibronectin fibrils, and a variety of other soluble proteins, influence many properties of cells, including their motility, proliferation, state of differentiation, and predisposition to apoptosis. In some cells, specialized forms of the pericellular matrix, termed ‘basement membranes’ or ‘basal laminae’, subserve a physical role, but these structures also influence cell function and fate.
During the past 10–15 years, increasing attention has been paid to a group of ‘matrix’ proteins that modulate cell function but do not appear to contribute directly to the organization or physical properties of structures such as fibrils or basal laminae. These proteins have been termed ‘matricellular’ proteins to emphasize their roles as regulators of cell function 2., 3•.. To the original group of matricellular proteins, thrombospondin-1 (TSP1), SPARC (secreted protein, acidic and rich in cysteine; also known as osteonectin), and tenascin-C [4], can now be added TSP2, osteopontin (OPN), and possibly the CCN (cyr-61, CTGF [connective tissue growth factor], Nov) family of proteins [5] and tenascin X [6]. The properties of matricellular proteins that justify their inclusion in a separate functional category of ECM proteins are summarized in Table 1. However, given the ability of proteins to perform both structural and cell-regulatory roles, and the ingenuity of nature in recruiting proteins to perform functions that surprise us, such groupings should remain fluid. Much of the justification for distinguishing matricellular from matrix proteins has come from an appreciation of the unusual phenotypes of mice that lack a matricellular protein. These phenotypes (Table 2) are superficially mild and are consistent with a minimal contribution of the proteins to structural integrity. Several recent comprehensive reviews of individual members of the matricellular protein family have been published 5., 7., 8., 9., 10., 11., 12•., 13., 14.. In this review, we focus on the TSPs and SPARC; but we discuss recent work on the other proteins, in an attempt to deduce common mechanisms in the action of matricellular proteins.
Section snippets
Cell adhesion, migration and chemotaxis
In contrast to matrix proteins that generally foster strong cell adhesion, TSP1 and 2, tenascin-C and SPARC support a state of intermediate adhesion, characterized by disruption of focal adhesions and a reorganization of actin stress fibers 4., 15••.. Recent experiments have demonstrated an interaction between the amino-terminal heparin-binding domain of TSP1 and cell-surface calreticulin, and suggest that the resulting signals mediate disassembly of focal adhesions [16]. An analogous receptor
Matrix assembly and collagen fibrillogenesis
A prominent feature of the TSP2-null mouse is fragility of skin and laxity of tendons and ligaments (Table 2). Dermal collagen fibers are abnormal by light microscopy, and fibrils in both skin and tendons are larger in diameter and irregularly contoured [33]. Although TSP2 could not be detected as a collagen-fiber-associated protein by immunocytochemistry of uninjured skin, an association of the protein with collagen fibers was observed under conditions of increased synthesis, for example as
Regulation of proliferation and apoptosis
Most matricellular proteins appear to affect cell proliferation. Although it is highly probable that regulation of the cell cycle and modulation of cell adhesion are related responses to at least some matricellular proteins, precise mechanisms remain to be identified. It is now appreciated that signals from both integrins and growth factor receptors are necessary for G1→ S-phase transition and cell proliferation [31•]. Synergy between these receptors results from input generated by the binding
Binding/activation of growth factors and cytokines; regulation of growth factor production
SPARC has been shown to abrogate cellular responses to PDGF, VEGF and FGF-2, although the mechanisms vary and are incompletely defined [8]. In addition to its high-affinity binding to PDGF-B and VEGF, SPARC was shown to compete for the binding of PDGF to fibroblasts, and to interact specifically and saturably with SMC via its carboxy-terminal domain 8., 40•.. Consequences of the binding of SPARC to VEGF165 include prevention of VEGF–VEGFR1 (VEGF receptor 1) interaction, inhibition of VEGFR1
Angiogenesis and tumor growth
It is now generally accepted that most primary and metastatic neoplasms require an angiogenic response on the part of the host for their growth [55]. As inhibitors of EC proliferation, TSP1 and TSP2 were prime candidates for studies of their efficacy as endogenous inhibitors of tumor angiogenesis. The incidence of tumors in mice bearing the neu oncogene under the control of the MMTV promoter was increased after these mice were placed on a TSP1-null background, and was reduced by co-expression
Conclusions and future directions
The information that cells receive from their environment is provided by a variety of molecules that range from growth factors and cytokines to adhesive proteins and proteoglycans. Until recently, little attention was paid to mechanisms that might coordinate or modulate this flow of information, either at the level of cell-surface receptors or at a distance from the cell. We suggest that matricellular proteins perform this regulatory function in different ways, some of which have been discerned
Acknowledgements
We thank A Agah, L Armstrong, T Kyriakides, J Lawler and J Murphy-Ullrich, for helpful comments on the manuscript. Original studies from the authors’ laboratories were supported by National Institutes of Health grants AR 45418, HL 59475, EY 13180, GM 40711, and National Science Foundation grant EEC 9529161.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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