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Matricellular proteins: an overview
Matrix Biology 19 Ž2000. 555᎐556
Introduction
Matricellular proteins: an overview Paul BornsteinU Departments of Biochemistry and Medicine, Uni¨ ersity of Washington, Seattle WA 98195, USA Accepted 27 July 2000
The cluster of reviews that appears in this and subsequent issues of Matrix Biology deals with the topic of matricellular proteins. The term ‘matricellular’ was coined in 1995 to denote a subset of extracellular matrix ŽECM. proteins whose properties could be distinguished from structural macromolecules on the one hand and more bioactive proteins such as growth factors, cytokines, and proteases on the other ŽBornstein, 1995.. A short list of these proteins includes those under review in this series, i.e. thrombospondins ŽTSP. 1 and 2, SPARC, tenascin C, and osteopontin. However, this list could probably be lengthened by addition of other members of the tenascin family and by members of the novel CCN family of ECM-associated proteins, as exemplified by its prototype, CYR61 ŽLau and Lam, 1999.. While the classification of proteins becomes increasingly fluid as new functions are discovered for proteins whose biological role was thought to be completely understood, viz. the participation of cytochrome c in apoptosis ŽGoldstein et al., 2000., there are a number of properties of matricellular proteins that justify their segregation into a subcategory of ECM proteins. Matricellular proteins bridge the functional divide between structural macromolecules and growth factors, cytokines, and proteases ŽFig. 1.. Thus, matricellular proteins do not subserve primarily structural roles in the sense that they constitute integral components of physical entities such as basement membranes or fibers. Rather, these proteins function contextually as adapters and modulators of cell᎐matrix interactions ŽSage and Bornstein, 1991.. We preU
Corresponding author. Tel.: q1-206-543-1789; fax: q1-206685-4426. E-mail address: [email protected] ŽP. Bornstein..
sume that the complex nature of their functions, as described in this series of reviews, derives from their ability to interact with more than one cell-surface receptor, and with cytokines, growth factors, proteases, and structural proteins. The contextual nature of their functions thus can reflect the composition of the matrix, the availability of bioactive molecules, and the expression of different cell-surface receptors in diverse cellular environments. In contrast to mice with a targeted disruption of a gene encoding a structural protein, which usually display a lethal or severe phenotype, mice that are null for a matricellular protein appear surprisingly normal on superficial examination in a laboratory setting. This finding can be accounted for by the fact that, as a rule, the repertoire of proteins with overlapping structural functions is more limited than that of proteins with overlapping modulatory functions. Presumably, the complex compensatory adjustments required for survival of an organism faced with the absence of a regulatory protein are more likely to be successful than compensation for lack of a structural protein, since regulatory pathways are complex networks with many opportunities for compensatory interactions. Nevertheless, as the phenotypes of mice that lack specific matricellular proteins have been studied more closely, many abnormalities have been observed which reflect the diverse biological functions of these proteins. In some cases the findings are both striking and unexpected, and they provide unusual opportunities to explore new ways in which extracellular proteins can influence cell function and tissue morphogenesis. Thus, as described in this series of reviews, mice that lack SPARC have been found to develop cataracts; TSP2-null mice display a bleeding defect and abnormalities in fibroblast adhesion; os-
0945-053Xr00r$ - see front matter 䊚 2000 Elsevier Science B.V. All rights reserved. PII: S 0 9 4 5 - 0 5 3 X Ž 0 0 . 0 0 1 0 3 - 7
556
P. Bornstein r Matrix Biology 19 (2000) 555᎐556
known functions of these proteins prior to the analysis of the knockout phenotypes. These findings therefore underscore the unusual biological roles that matricellular proteins play in the extracellular matrix. References Fig. 1. A schematic representation of the pericellular environment and the major categories of proteins and other structural macromolecules that are present in the vicinity of cells. Matricellular proteins interact with both structural macromolecules and growth factors, cytokines and proteases, and bridge the functional divide between these two other categories of molecules.
teopontin-null mice show reduced T cell-mediated immunity and increased dystrophic calcification, and tenascin-C-null mice show subtle neurological defects and a suppression of hematopoetic activity. Some of these findings could not have been predicted from the
Bornstein, P., 1995. Diversity of function is inherent in matricellular proteins: an appraisal of thrombospondin 1. J. Cell Biol. 130, 503᎐506. Goldstein, J.C., Waterhouse, N.J., Juin, P., Evan, G.I., Green, D.R., 2000. The coordinate release of cytochrome c during apoptosis is rapid, complete and kinetically invariant. Nat. Cell Biol. 2, 156᎐162. Lau, L.F., Lam, S.T., 1999. The CCN family of angiogenic regulators: the integrin connection. Exp. Cell Res. 248, 44᎐57. Sage, E.H., Bornstein, P., 1991. Extracellular proteins that modulate cell-matrix interactions: SPARC, tenascin and thrombospondin. J. Biol. Chem. 266, 14831᎐14834.
Introduction
Matricellular proteins: an overview Paul BornsteinU Departments of Biochemistry and Medicine, Uni¨ ersity of Washington, Seattle WA 98195, USA Accepted 27 July 2000
The cluster of reviews that appears in this and subsequent issues of Matrix Biology deals with the topic of matricellular proteins. The term ‘matricellular’ was coined in 1995 to denote a subset of extracellular matrix ŽECM. proteins whose properties could be distinguished from structural macromolecules on the one hand and more bioactive proteins such as growth factors, cytokines, and proteases on the other ŽBornstein, 1995.. A short list of these proteins includes those under review in this series, i.e. thrombospondins ŽTSP. 1 and 2, SPARC, tenascin C, and osteopontin. However, this list could probably be lengthened by addition of other members of the tenascin family and by members of the novel CCN family of ECM-associated proteins, as exemplified by its prototype, CYR61 ŽLau and Lam, 1999.. While the classification of proteins becomes increasingly fluid as new functions are discovered for proteins whose biological role was thought to be completely understood, viz. the participation of cytochrome c in apoptosis ŽGoldstein et al., 2000., there are a number of properties of matricellular proteins that justify their segregation into a subcategory of ECM proteins. Matricellular proteins bridge the functional divide between structural macromolecules and growth factors, cytokines, and proteases ŽFig. 1.. Thus, matricellular proteins do not subserve primarily structural roles in the sense that they constitute integral components of physical entities such as basement membranes or fibers. Rather, these proteins function contextually as adapters and modulators of cell᎐matrix interactions ŽSage and Bornstein, 1991.. We preU
Corresponding author. Tel.: q1-206-543-1789; fax: q1-206685-4426. E-mail address: [email protected] ŽP. Bornstein..
sume that the complex nature of their functions, as described in this series of reviews, derives from their ability to interact with more than one cell-surface receptor, and with cytokines, growth factors, proteases, and structural proteins. The contextual nature of their functions thus can reflect the composition of the matrix, the availability of bioactive molecules, and the expression of different cell-surface receptors in diverse cellular environments. In contrast to mice with a targeted disruption of a gene encoding a structural protein, which usually display a lethal or severe phenotype, mice that are null for a matricellular protein appear surprisingly normal on superficial examination in a laboratory setting. This finding can be accounted for by the fact that, as a rule, the repertoire of proteins with overlapping structural functions is more limited than that of proteins with overlapping modulatory functions. Presumably, the complex compensatory adjustments required for survival of an organism faced with the absence of a regulatory protein are more likely to be successful than compensation for lack of a structural protein, since regulatory pathways are complex networks with many opportunities for compensatory interactions. Nevertheless, as the phenotypes of mice that lack specific matricellular proteins have been studied more closely, many abnormalities have been observed which reflect the diverse biological functions of these proteins. In some cases the findings are both striking and unexpected, and they provide unusual opportunities to explore new ways in which extracellular proteins can influence cell function and tissue morphogenesis. Thus, as described in this series of reviews, mice that lack SPARC have been found to develop cataracts; TSP2-null mice display a bleeding defect and abnormalities in fibroblast adhesion; os-
0945-053Xr00r$ - see front matter 䊚 2000 Elsevier Science B.V. All rights reserved. PII: S 0 9 4 5 - 0 5 3 X Ž 0 0 . 0 0 1 0 3 - 7
556
P. Bornstein r Matrix Biology 19 (2000) 555᎐556
known functions of these proteins prior to the analysis of the knockout phenotypes. These findings therefore underscore the unusual biological roles that matricellular proteins play in the extracellular matrix. References Fig. 1. A schematic representation of the pericellular environment and the major categories of proteins and other structural macromolecules that are present in the vicinity of cells. Matricellular proteins interact with both structural macromolecules and growth factors, cytokines and proteases, and bridge the functional divide between these two other categories of molecules.
teopontin-null mice show reduced T cell-mediated immunity and increased dystrophic calcification, and tenascin-C-null mice show subtle neurological defects and a suppression of hematopoetic activity. Some of these findings could not have been predicted from the
Bornstein, P., 1995. Diversity of function is inherent in matricellular proteins: an appraisal of thrombospondin 1. J. Cell Biol. 130, 503᎐506. Goldstein, J.C., Waterhouse, N.J., Juin, P., Evan, G.I., Green, D.R., 2000. The coordinate release of cytochrome c during apoptosis is rapid, complete and kinetically invariant. Nat. Cell Biol. 2, 156᎐162. Lau, L.F., Lam, S.T., 1999. The CCN family of angiogenic regulators: the integrin connection. Exp. Cell Res. 248, 44᎐57. Sage, E.H., Bornstein, P., 1991. Extracellular proteins that modulate cell-matrix interactions: SPARC, tenascin and thrombospondin. J. Biol. Chem. 266, 14831᎐14834.