Scube3, or signal peptide-CUB-EGF domain-containing protein 3, is a multifunctional secreted glycoprotein. It functions as a co-receptor for various growth factors and is involved in multiple signaling pathways, such as TGF-β, BMP, and FGF signaling. These pathways are crucial for growth, morphogenesis, and development of tissues and organs [1,2,3,5,6,9].

In hair follicle development, Hedgehog signaling upregulates Scube3 in dermal papilla fibroblasts of growing follicles. Scube3, through a TGF-β mechanism, contributes to hair growth acceleration and follicle multiplication [1].

In tooth development, epithelium-derived Scube3 translocates to the mesenchyme, promoting proliferation, migration, and polarized odontoblastic differentiation of dental mesenchymal stem cells [2].

In hepatocellular carcinoma, knockdown of Scube3 inhibits cell proliferation, promotes apoptosis, and arrests the cell cycle via the TGFβ/PI3K/AKT/GSK3β pathway [3].

In breast cancer, high Scube3 expression is associated with poor prognosis [4].

Loss-of-function of Scube3 in humans and mice leads to a syndromic disorder with reduced growth, skeletal and dental anomalies due to defective BMP signaling [5].

In human bone marrow mesenchymal stem cells, Scube3 promotes osteogenic differentiation and mitophagy through the BMP2/TGF-β signaling pathway [6].

In tongue squamous cell carcinoma, Scube3 promotes tumor growth via the CEBPA/CCL2/STAT3 axis [7].

In systemic lupus erythematosus, SCUBE3 variants may be a genetic susceptibility factor, and its mRNA expression is reduced in patients [8].

In fast muscle development, knockdown of Scube3 in zebrafish suppresses fast muscle differentiation by modulating FGF8 signaling [9].

In non-small cell lung cancer, high Scube3 expression is associated with lymph node involvement, advanced TNM stages, and poor prognosis, potentially regulating epithelial-mesenchymal transition [10].

In conclusion, Scube3 plays essential roles in multiple biological processes such as tissue development, cell differentiation, and mitophagy, and is involved in various diseases including cancer, systemic lupus erythematosus, and developmental disorders. Studies using gene knockout or knockdown models in mice and zebrafish have been crucial in revealing these functions, providing insights into potential therapeutic targets for related diseases.