Fig. 3

Pathological involvement of SCUBE1. A SCUBE1 modulates BMP signaling activity in a context-dependent manner. When expressed in “signal-producing” cells, the C-terminal CR and CUB domains are released by an as yet undetermined proteinase, allowing them to bind and inhibit the secretion of mature BMP into the culture medium. SCUBE1 therefore acts as an antagonist for long-range BMP signaling activity during brain development [20]. In contrast, when SCUBE1 is expressed in “signal-responding” cells, it forms a complex with BMP ligand and its receptors. SCUBE1 thereby acts as a BMP coreceptor to augment BMP signaling activity critical for protecting against kidney ischemia–reperfusion (I/R) injury or for primitive hematopoiesis [8, 49]. B Proposed model for adhesive function of SCUBE1 in platelet aggregation and thrombus formation. Under normal conditions, plasma SCUBE1 is expressed at low levels primarily by endothelial cells and platelets. In addition, SCUBE1 is stored in the α-granules of resting platelets. Upon pathological stimulation, activated platelets secrete large amounts of SCUBE1 into the circulation and high levels of SCUBE1 are also found on the platelet surface. The surface SCUBE1 on nearby activated platelets is trans-homophilically crosslinked by soluble SCUBE1, acting through its sticky EGF-like repeats to promote platelet agglutination and stabilize platelet plugs. Targeting the adhesive modules of SCUBE1 with a specific monoclonal antibody might be a potentially useful anti-thrombotic strategy [72, 86]. C SCUBE1-promoted BMP signaling protects against kidney ischemia/reperfusion (I/R) injury. I/R-induced SCUBE1 protein in proximal tubular epithelial cells serves as a BMP coreceptor to enable renoprotective BMP7 signaling, which stimulates epithelial repair and regeneration through proliferative, anti-apoptotic, and anti-inflammatory effects [49]. D Potential immunotherapy strategy and the pathological function of surface SCUBE1 in MLL-r leukemias. Left: SCUBE1 is an immediate downstream target of the HOXA9/MEIS1 transcriptional regulatory complex, which is activated by MLL-fusion proteins like MLL-AF9 and is crucial for sustaining leukemic transition. Surface SCUBE1 functions as a FLT3 coreceptor in MLL-r leukemias, facilitating the interaction between FLT3 ligand and FLT3. This action increases downstream LYN-AKT activation (tyrosine phosphorylation) to enhance leukemic cell proliferation and survival, thereby promoting leukemogenesis. Right: An anti-SCUBE1 ADC conjugated to an antimitotic agent (MMAE) leads to significant cell killing specifically in MLL-AF9 leukemias. Thus, surface expression of SCUBE1 on MLL-r leukemia cells may be useful as a target for immunotherapy. ADC antibody–drug conjugate; MMAE monomethyl auristatin E. MLL-r, mixed-lineage leukemia gene-rearranged; BMP bone morphogenetic protein 1