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 pathways [1-9]. It plays a crucial role in development, including hair follicle, tooth, bone, and muscle development, and is also implicated in various disease processes like cancer and autoimmune diseases [1-8]. Genetic models, especially mouse models, have been instrumental in studying its function.

In hair follicle development, Hedgehog signaling-induced upregulation of Scube3 in dermal papilla fibroblasts promotes hair growth, with Scube3 protein injection alone sufficient to trigger new hair growth [1]. In tooth development, epithelium-derived Scube3 translocates to the mesenchyme, promoting dental mesenchymal stem cell proliferation, migration, and odontoblastic differentiation [2]. In hepatocellular carcinoma, knockdown of Scube3 inhibits cell proliferation, promotes apoptosis, and arrests the cell cycle, suggesting its role in cancer progression [3]. In breast cancer, high Scube3 expression indicates poor prognosis [4]. In human bone marrow mesenchymal stem cells, Scube3 promotes osteogenic differentiation and mitophagy through the BMP2/TGF-β signaling pathway [5]. Loss-of-function variants in Scube3 in humans and Scube3-/-mice lead to a developmental disorder with craniofacial, dental, and skeletal defects due to impaired BMP-mediated chondrogenesis and osteogenesis [6]. In tongue squamous cell carcinoma, silencing Scube3 restrains cell proliferation, migration, and invasion [7]. In Chinese populations, variants in Scube3 are associated with systemic lupus erythematosus susceptibility, and its mRNA expression is lower in patients [8]. In zebrafish, knockdown of scube3 suppresses fast muscle development by inhibiting FGF signaling [9]. In non-small cell lung cancer, high Scube3 expression is correlated with lymph node involvement, advanced TNM stages, and poor prognosis [10].

In conclusion, Scube3 is essential for normal development and is involved in various disease processes. Gene knockout and conditional knockout mouse models, along with other functional studies, have significantly contributed to understanding its role in hair, tooth, bone, and muscle development, as well as in cancer and autoimmune diseases. These insights provide potential targets for therapeutic interventions in related diseases.