SCUBE3

This gene encodes a member of the signal peptide, complement subcomponents C1r/C1s, Uegf, bone morphogenetic protein-1 and epidermal growth factor-like domain containing protein family. Overexpression of this gene in human embryonic kidney cells results in secretion of a glycosylated form of the protein that forms oligomers and tethers to the cell surface. This gene is upregulated in lung cancer tumor tissue compared to healthy tissue and is associated with loss of the epithelial marker E-cadherin and with increased expression of vimentin, a mesenchymal marker. In addition, the protein encoded by this gene is a transforming growth factor beta receptor ligand, and when secreted by cancer cells, it can be cleaved in vitro to release the N-terminal epidermal growth factor-like repeat domain and the C-terminal complement subcomponents C1r/C1s domain. Both the full length protein and C-terminal fragment can bind to the transforming growth factor beta type II receptor to promote the epithelial-mesenchymal transition and tumor angiogenesis. Alternative splicing results in multiple transcript variants.

Full Name

signal peptide, CUB domain, EGF-like 3

Function

Is a positive regulator of the BMP signaling pathway, required for proper chondrogenesis, osteogenesis and skeletal development. It acts as coreceptor for BMP ligands, particularly BMP2 and BMP4, facilitating their interactions with BMP type I receptors (PubMed:33308444).
It is required for ligand-induced recruitment of BMP receptors to lipid rafts (By similarity).
Binds to TGFBR2 and activates TGFB signaling. In lung cancer cells, could serve as an endogenous autocrine and paracrine ligand of TGFBR2, which could regulate TGFBR2 signaling and hence modulate epithelial-mesenchymal transition and cancer progression.

Biological Process

Biological Process positive regulation of BMP signaling pathwayManual Assertion Based On ExperimentIMP:UniProtKB
Biological Process positive regulation of osteoblast differentiationManual Assertion Based On ExperimentIMP:UniProtKB
Biological Process signal transductionManual Assertion Based On ExperimentIBA:GO_Central

Cellular Location

Secreted
Cell surface

Involvement in disease

Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2 (SSFSC2):
An autosomal recessive disorder characterized by reduced growth, skeletal abnormalities, a distinctive craniofacial appearance, and dental anomalies. Cardiac anomalies have been reported in some patients.

PTM

N-glycosylated.
Proteolytic cleavage produces a CUB-containing C-terminal fragment that retains the ability to bind to TGFBR2. This reaction is catalyzed in vitro by MMP2 and, to a lesser extent, by MMP9.