CUB domain-containing protein 1 (CDCP1) binds transforming growth factor beta family members and increase TGF-β1 signaling pathway

Highlights: • CUB domains of CDCP1 bind directly to different TGF-β proteins. • Binding of TGF-β1 to CDCP1 increase TGF-β1 signaling pathway. • Inhibition of TGFRI and SMAD2 KO blocks CDCP1 ability to increase TGF-β1 signaling pathway. -- Abstract: CUB domains are most exclusively found in secreted proteins and in a few transmembrane proteins. These domains are approximately 110 amino acids long and have four conserved cysteines that form a β-sandwich fold. CUB domains proteins are involved in a wide range of biological functions. We have shown that CUB domains from Tolloid/BMP1 can bind BMP4 and block BMP signaling in the developing frog embryo. CUB domain-containing protein 1 (CDCP1) is one of the few transmembrane glycoprotein that contains three extracellular CUB domains and regulates anchorage-independent growth and cancer cell migration through activation of Src kinases. In the extracellular space, only a few proteins were found to interact with CDCP1 and at the moment no ligand was found. We demonstrate by using real time protein interaction on BIAcore chip that CDCP1 CUB domains bind directly to TGF-β1 and BMP4. CDCP1 enhances TGF-β1 signaling reporter activity and phosphorylated Smad2 levels but does not modulate BMP signaling pathway. CDCP1 actions on TGF-β/Smad2 signaling are dependent on Smad2 and TGFRI and do not require Src or PKCδ binding. Our findings uncover a new co-receptor for TGF-β1 and bring up new questions on whether CDCP1 cooperates with TGF-β1 to promote cancer progression.