SPARC (secreted protein acidic and cysteine-rich)

Note	SPARC encodes a cysteine-rich acidic matrix-associated protein that belongs to a family of SPARC-related proteins composed of others six members, that include SPOCK1, SPOCK2, SPOCK3, SPARCL1, SMOC1, SMOC2 (testican-1, -2, -3, SPARC-like 1 (or hevin, Mast9), and SPARC-related modular calcium binding (SMOC)-1, and -2). All members of this protein family share the three similar domains (Bradshaw and Sage, 2001; Brekken and Sage, 2000). SPARC protein is required for the collagen in the bone to become calcified. SPARC is also involved in extracellular matrix synthesis and remodeling being associated with the promotion of changes in cell shape. SPARC protein has been associated with tumor suppression but has also been correlated with metastasis based on changes to cell shape which can promote tumor cell invasion (GeneCard RefSeq). molecular weight: 303aa, 43 kDa; Isoelectric point: 4.4719. Although, after cleavage of the signal sequence, SPARC is a 32-kDa protein (Mason et al. 1986), the secreted form is identified as a 43 kDa protein on SDS-PAGE, which is due to the addition of carbohydrate (Sage et al. 1984). NP_003109.1: molecular weight: 303 aa; NP_001296372.1: molecular weight: 302 aa; NP_001296373.1: molecular weight: 341 aa
	Figure 1 - Schematic representation of the 303 aa human SPARC protein with its functional and structural domains. Box represents the three functional domains: acidic domain (18-52aa), follistatin-like (53-137aa), extracellular Ca2+-binding (138- 286aa). The first seventeen amino acids correspond to the signaling peptide. Stars and triangles represent some of the structural domains: yellow and green stars represent collagen-binding and high-affinity Ca2+-binding residues, respectively. Triangles represent cleavage sites for cathepsin (blue), MMP2, MMP3, MMP7, MMP9, and MMP13 (red), and MMP3 (purple). (based on Brekken and Sage, 2001; Chlenski and Cohn, 2010)
Description	SPARC is a 43kDa protein, composed of 303 aminoacids. The first 17 amino acids containing the signaling peptide sequence is removed during protein processing. SPARC protein has three structural domains: N-terminal domain (NT; aa 3-51) encoded by exons 3 and 4, follistatin-like domain (FS; 53-137 aa) encoded by exons 5 and 6, the Extra Cellular domain (EC; aa 138-286) encoded by exons 7 to 9. It has eleven collagen- and six high-affinity Ca2+ binding residues. Also, the protein presents cleavage sites for cathepsin and members of the metalloproteinases family (Brekken and Sage, 2000; figure 1). The NT domain binds hydroxyapatite and calcium ions. The FS domain contains several internal disulfide bonds that stabilize two weakly interacting modules. The N-terminus region of the FS domain has a very twisted-hairpin structure that is linked by disulfide bonds at cysteines 1-3, and 2-4. This distribution of disulfide bonds makes the FS-domain structurally homologous to epidermal growth factor (EGF)-like domain of factor IX, a coagulation factor. At the other end of the FS-domain, its C-terminus region has structural similarity to Kazal family of serine proteases. It has antiparallel alpha-helices connected to small three-stranded antiparallel alpha-sheets with disulfide bonds linking cysteines 5-9, 6-8, 7-10. The EC domain contains two E-F hand motifs that bind calcium with high affinity, and comprise almost entirely of alpha-helices (Hohenester et al., 1997).
Expression	The evaluation of the expression pattern of SPARC protein and mRNA during human embryonic and fetal development revealed that it is usually expressed in tissues undergoing rapid proliferation (Mundlos et al., 1992). These authors also showed that earlier developmental stages showed a more general distribution, changing to more heterogeneity expression pattern in later stages. SPARC expression was observed in bone, cartilage, teeth, kidney, gonads, adrenal gland, lung, eye, vessels (Mundlos et al., 1992). In adults SPARC is expressed in different tissues and organs, including bone marrow, whole blood, lymph node, thymus, brain, cerebellum, retina, heart, smooth muscle, skeletal muscle, spinal cord, intestine, colon, adipocyte, kidney, liver, pancreas, thyroid, salivary gland, skin, ovary, uterus, placenta, cervix and prostate (Wang et al, 2014). It is also described that SPARC is expressed by different cell types including active osteoblasts, bone marrow progenitor cells, odontoblasts endothelial cells, fibroblasts, pericytes, astrocytes and macrophages (McCurdy et al. 2010; Rosseta and Bradshaw, 2016). In cancer, according to PrognoScan database, SPARC expression was observed in bladder, blood, brain, breast, colorectal, eye tumors, glioma, head and neck cancer, lung, esophagus, ovarian, and skin cancer tissues (Wang et al., 2014). There are evidences that SPARC expression is transcriptionally regulated by methylation in different types of neoplasia such as ovarian cancer (Socha et al, 2009), pancreatic cancer (Vaz et al, 2015), hepatocellular carcinoma (Zhang et al, 2012) colorectal (Cheetham et al., 2008) and breast (Matteucci et al, 2016). Loss of heterozygosity (LOH) at 5q has been demonstrated in pancreatic cancer (Hahn et al., 1995), in pulmonary fibrosis (Demopoulos et al., 2002) and myelodysplastic syndromes (Giagounidis et al., 2014).
Localisation	SPARC is a secreted glycoprotein found mainly in the extracellular compartment. However, it has also been described to be localized both to cell nucleus and to cytoplasm (Hudson et al., 2005; Baldini et al. 2008).
Function	SPARC is an evolutionarily conserved matricellular glycoprotein that is involved in diverse biological processes, including tissue remodeling, wound repair, morphogenesis, cell differentiation, proliferation, migration, and angiogenesis. Matricellular glycoprotein proteins are a family of proteins that can be associated with structural elements and mediates cell-matrix interaction rather than functions as extracellular matrix (ECM) structural elements (Bornstein, 1995). SPARC was first described in skeletal tissue as a bone-specific protein that binds selectively to both hydroxyapatite and collagen (Termine et al., 1981). Posteriorly, it was shown that this protein is broadly expressed both in mineralized and non-mineralized tissues being associated to ECM, regulating cell-matrix interactions and cellular functions, than contributing to ECM organization (Bornstein, 2000; Bradshaw, 2012). SPARC has also been shown to regulate the activity of matrix metalloproteinases (MMP), a family of enzymes capable of breaking down proteins, such as collagen, normally found in ECM and considered to be the mediators of ECM proteolysis and turnover. Angiogenesis, healing and metastasis, processes that require ECM restructuring are associated with higher SPARC production. The influence of SPARC on MMP-1, MMP-3, and MMP-9 activity was first described by Tremble et al., 1993. Further studies were carried out in transformed cells and tumor, and it was demonstrated that SPARC could increase MMP-2 activity in glioma cells and breast cancer cells but not in melanoma cells (McClung et al., 2007, Nischt et al., 2001, Gilles et al., 1998).
Homology	The human SPARC gene shows 92% and 31% identity with the mouse and nematode homologs, respectively. SPARC is conserved in a wide variety of evolutionarily diverse organisms (e.g., C. elegans, Drosophila, brine shrimp, trout, chicken, mice, and humans), suggesting that it plays an important function in multicellular biology (Bradshaw and Sage, 2001).

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