Molecules in focus
SPARC (osteonectin/BM-40)

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Abstract

SPARC (Secreted ProteinAcidic and Rich in Cysteine) is a prototype of a family of biologically active glycoproteins that bind to cells and to extracellular matrix (ECM) components. It is expressed spatially and temporally during embryogenesis, tissue remodeling and repair. SPARC is a modular protein (34 kDa) comprised of three structural domains, one or more of which are implicated in the regulation of cell adhesion, proliferation, matrix synthesis/tumover. Rapid proteolysis of SPARC by extracellular proteases accounts for its transient detection in the extracellular environment. The proposed roles of SPARC in the development of cataracts and the regulation of angiogenesis during wound healing and tumor growth account for the recent attention it has received from the biomedical community.

Introduction

SPARC, also known as osteonectin, is an extracellular matrix-associated glycoprotein first identified by Termine and coworkers as a major noncollagenous constituent of bovine bone [1]. Subsequently, SPARC was isolated as a 43 kDa “culture shock” glycoprotein from proliferating bovine aortic endothelial cells [2] and porcine fibroblasts in vitro [3]. Soon after, cDNA sequence comparison revealed that SPARC, the major secreted product of differentiated mouse embryo parietal endoderm cells, the 43 kDa endothelial culture shock protein, BM-40, a protein from the basement membrane producing EHS tumor, and osteonectin were orthologs [4], [5].

Section snippets

Structure

SPARC is a product of a single-copy gene mapped to mouse chromosome 11 and to the long arm of human chromosome 9. Sequencing analysis of the SPARC gene in bovine, mouse, and human has revealed a high degree of sequence identity and an absence of canonical TATA and CAAT box sequences. A major mRNA of 2.2 kb and a less abundant mRNA of 3.0 kb are characteristically transcribed from this single gene [6]. Shorter mRNA sizes of 1.6 and 1.1 kb have been reported in frogs and nematods, respectively.

Synthesis and degradation

SPARC expression is believed to be regulated spatially and temporally throughout development. Localization by in situ hybridization and immunohistochemistry has revealed synthesis of high levels of SPARC mRNA and protein, respectively, by a variety of tissues undergoing remodeling during normal development or in response to injury [8]. High levels of the protein are detected in developing bones and teeth, activated human platelets and megakaryocytes, and in the “culture shock” which occurs when

Biological function

In addition to the established classical function of SPARC as a Ca+2-binding protein in the development of ossified and mineralized tissues, recent studies in cultured vascular cells have suggested a potential seminal role for this protein in tissue morphogenesis and in cellular differentiation (reviewed in [8]. SPARC expression is believed to modulate reversible interactions between cells and ECM through: (a) inhibiting cell spreading and disassembly of focal adhesions — specialized sites that

Possible medical applications

Although the development of cataracts in humans has not yet been linked to the SPARC gene, the results in SPARC-null mice indicate that SPARC is of fundamental importance to lenticular development. A more definitive role for this protein in pathological conditions is supported by studies demonstrating that SPARC overexpression is associated with neovascularization during wound healing and with neoplastic progression of human malignant tumors (breast and colorectal cancer) and melanoma [17], [18]

Acknowledgements

I thank Helene Sage for a critical reading of the manuscript. I gratefully acknowledge the financial support of the American Cancer Society (grant 91-020-06-IRG) and National Institutes of Health (grant P01-HL18645).

References (19)

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SPARC (Secreted Protein Acidic and Rich in Cysteine).

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