Signal peptide-CUB-EGF-like domain-containing protein 3 (SCUBE3) is a secreted glycoprotein that is highly expressed in osteoblasts. It can form homooligomers and heterooligomers with SCUBE1, which stably associate with the peripheral cell surface (Wu et al. 2004). Overexpressesion of Scube3 has been linked to significant murine cardiac hypertrophy (Yang et al. 2007). The C-terminal portion of SCUBE3 can physically interact with Transforming growth factor beta-1 (TGFB1) and promote TGFB1-mediated transcriptional activation in vitro (Yang et al. 2007). Consistent with this, the phosphorylated and total protein levels of Smad2, a well-known TGFB1 downstream signaling molecule, are elevated in Scube3 transgenic mouse heart under pressure overload. SCUBE3 may be a component of the regulatory mechanisms for active TGFB1 bioavailability, either systemically or locally in cardiac tissues, under baseline conditions and during pathological stresses. A Scube3 mutant mouse line (carrying a missense mutation in exon 8) has phenotypic alterations that suggest a role of Scube3 in bone metabolism and morphology, hearing, and renal function. The observed morphological abnormalities of the skeleton, impaired bone metabolism and hearing impairments are comparable with the rare metabolic bone disorder Paget disease, which is associated with the chromosomal region that includes SCUBE3 (Fuchs et al. 2016).