Secreted Modular Calcium-Binding Proteins in Pathophysiological Processes and Embryonic Development
Secreted modular calcium-binding proteins (SMOCs) are extracellular glycoproteins that belong to the SPARC (secreted protein, acidic, and rich in cysteine) family. In humans, SMOCs include two isoforms, SMOC1 and SMOC2, which play critical roles in various cellular functions, embryonic development, and disease states. This review provides a comprehensive overview of the molecular structures, expression patterns, and functional roles of SMOC1 and SMOC2 in embryonic development, homeostasis, and human diseases. Additionally, the potential therapeutic applications of targeting SMOCs in cancer and birth defects are discussed.
Molecular Structures and Expression of SMOCs
SMOC1 and SMOC2 are extracellular glycoproteins with distinct structural domains and tissue-specific expression patterns. SMOC1 was first identified in 2002 and is encoded by a gene located on chromosome 14q24.2. The SMOC1 protein consists of 434 amino acids and has a molecular weight of 48,000. It contains five structural domains: a follistatin-like domain, two thyroglobulin-like domains, a unique domain, and an EF-hand calcium-binding domain. SMOC1 is highly expressed in tissues such as the ovary, brain, thymus, heart, skeletal muscle, liver, and lung. It is also a component of the basement membrane and extracellular matrix, where it interacts with collagen IV through its extracellular calcium-binding (EC) domain.
SMOC2, on the other hand, was identified later and shares 55% DNA sequence homology with SMOC1. The SMOC2 gene is located on chromosome 6q27, and its protein structure includes domains similar to SMOC1, with the addition of a unique SMOC domain. SMOC2 is expressed throughout the human body, particularly in the basement membrane and extracellular matrix, where it co-localizes with fibronectin. It has also been identified as a marker of intestinal stem cells, suggesting its pleiotropic roles in various biological processes.
Functions of SMOCs in Embryonic Development
SMOC1 and SMOC2 play essential roles in embryonic development. SMOC1 is critical for post-gastrulation development in Xenopus by inhibiting bone morphogenetic protein (BMP) signaling. It is also involved in ocular and limb development in both humans and mice. During mouse embryogenesis, SMOC1 is expressed in the endodermal basement membrane zone and mesenchymal and epithelial cells derived from all three germ layers. SMOC2, in contrast, is expressed in mid-gestation embryos, particularly in the forelimb, hindlimb, somites, and branchial arches. Mutations in SMOC2 have been associated with developmental dental defects.
Molecularly, SMOCs regulate embryonic development through the Smad signaling pathway, which activates mitogen-activated protein kinase (MAPK) signaling during joint formation. SMOC1 acts as an antagonist of BMP signaling by mediating MAPK-mediated Smad phosphorylation. This modulation of BMP signaling is evolutionarily conserved, as demonstrated by the ability of human SMOC1 and SMOC2 to rescue phenotypes in Caenorhabditis elegans SMOC1 mutants.
SMOCs in Bone Calcification
SMOCs are also involved in bone calcification. SMOC1 is highly expressed in bone and bone marrow mesenchymal stem cells, where it promotes osteoblast differentiation and mineralization. Knockdown of SMOC1 inhibits osteoblast differentiation, while overexpression enhances it. SMOC1 expression peaks during the early stages of osteoblast differentiation but decreases in later stages, indicating its role in the initial phases of bone formation.
SMOC2, however, inhibits osteogenic differentiation and extracellular matrix mineralization through its EC domain. It downregulates the mineralization process in human umbilical vein endothelial cells, and its deficiency does not affect calvaria-derived MC3T3-E1 cell calcification. These findings suggest that SMOC2 may be more involved in preventing ectopic calcification rather than promoting bone development.
Role of SMOCs in Angiogenesis
SMOCs play a significant role in angiogenesis, the process of new blood vessel formation. SMOC1 promotes angiogenesis by regulating transforming growth factor-beta (TGF-β) signaling. Knockdown of SMOC1 attenuates endothelial cell sprouting and delays retinal angiogenesis in mice. SMOC1 also inhibits the expression of activin-like kinase 5 (ALK5) and promotes TGF-β signaling and ALK1 activation, leading to endothelial cell proliferation and angiogenesis.
SMOC2, on the other hand, synergizes with vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) to stimulate DNA synthesis and endothelial cell network formation. Overexpression of SMOC2 promotes cell migration and angiogenesis, while its inhibition reduces these processes. These findings highlight the pro-angiogenic effects of SMOCs, which contrast with the anti-angiogenic effects of SPARC.
SMOCs in Cell Cycle Regulation and Cell Attachment
SMOCs also regulate the cell cycle and cell attachment. SMOC2 is highly expressed during the G1/S phase of the cell cycle in fibroblasts, and its expression decreases during serum-stimulated cell cycle progression. SMOC2 ablation reduces cyclin D1 levels and PDGF-induced DNA synthesis, indicating its role in cell cycle regulation. SMOC2 is also required for the effective activation of integrin-linked kinase (ILK), which is essential for the G1/S transition of the cell cycle.
In terms of cell attachment, the EC domain of SMOC1 promotes the adhesion of skin HaCaT cells in a heparin sulfate-dependent manner. SMOC1 also enhances endothelial cell adhesion to collagen I, laminin-III, and Matrigel. SMOC2, however, selectively promotes the adhesion of epidermal cells through integrins αvβ6 and αvβ1 but does not affect fibroblast adhesion. The EC domain of SMOC2 also induces cell migration and wound healing.
SMOCs in Human Diseases
SMOCs are implicated in various human diseases, including birth defects, tissue inflammation, fibrosis, and cancer.
Birth Defects
Mutations in SMOC1 are associated with Waardenburg Anophthalmia Syndrome (WAS), a condition characterized by eye malformations and limb anomalies. SMOC1 mutations include nonsense, frame-shift, and missense mutations, which disrupt its function in embryonic development. A novel homozygous missense mutation in SMOC1 (c.812G>A; p.Cys271Tyr) has been identified in patients with WAS, further highlighting its role in developmental disorders.
Tissue Inflammation and Fibrosis
SMOCs are involved in tissue inflammation and fibrosis. SMOC1 expression is reduced in rat mesangial cells treated with interleukin-1 beta, and its knockdown attenuates TGF-β signaling and fibrosis. SMOC2, on the other hand, promotes kidney fibrosis and pulmonary fibrosis. Neutralization of SMOC2 attenuates TGF-β-induced fibrosis in NIH 3T3 cells, and SMOC2 deficiency reduces bleomycin-induced pulmonary fibrosis in mice. These findings suggest that SMOC2 is a key regulator of fibrosis and a potential therapeutic target.
Cancer Development and Progression
SMOCs play dual roles in cancer development and progression. SMOC2 is downregulated in gallbladder carcinoma and advanced breast cancer but upregulated in metastatic head and neck squamous cell carcinoma. SMOC2 modulates keratinocyte adhesion through integrins, which are critical for cancer stem cell maintenance and anoikis resistance. In colorectal cancer, SMOC2 overexpression is associated with tumor metastasis and liver invasion. SMOC1, on the other hand, is upregulated in oligodendrogliomas and astrocytic tumors and inhibits tenascin-C-induced migration of glioma cells.
In hepatocellular carcinoma (HCC), SMOC2 expression is upregulated and promotes tumor cell proliferation through the MAPK and AKT signaling pathways. However, another study found that SMOC2 expression is downregulated in HCC and associated with a favorable prognosis. These conflicting findings highlight the need for further research to clarify the role of SMOC2 in HCC.
In lung adenocarcinoma, SMOC2 is identified as a pro-metastatic matricellular protein. Knockdown of SMOC2 inhibits lung cancer metastasis, and its expression is regulated by the circadian transcription factor Arntl2. These findings suggest that SMOC2 is a potential therapeutic target for lung cancer metastasis.
Conclusions
SMOC1 and SMOC2 are extracellular matrix proteins with distinct roles in embryonic development, homeostasis, and disease processes. SMOC1 promotes osteoblast differentiation and angiogenesis, while SMOC2 inhibits osteogenic differentiation and plays a dual role in cancer development. Both SMOCs regulate cell cycle progression, cell attachment, and fibrosis, and their imbalance with SPARC determines pathological outcomes in diseases such as cancer and fibrosis.
Future research should focus on elucidating the molecular mechanisms by which SMOCs regulate cell signaling and interact with growth factors. Additionally, the development of functionally glycosylated SMOC proteins is essential for advancing our understanding of their biological roles and therapeutic potential. Targeting SMOCs may provide new avenues for treating human cancers, birth defects, and fibrotic diseases.
doi.org/10.1097/CM9.0000000000000472
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