Ph.D., University of Texas Southwestern Medical Center at Dallas
Postdoctoral Fellow, Genentech, Inc.
This laboratory is interested in understanding the basic and translational biology of a secreted and membrane SCUBE (signal peptide-CUB-EGF domain-containing protein) family originally identified from endothelial cells (ECs). Three different members (SCUBE1 to 3) have been identified and appear to be evolutionarily conserved in vertebrates from zebrafish and mice to humans. We showed that SCUBEs are multi-functional proteins depending on their subcellular localization and distribution. For example, plasma SCUBE1 released from activated platelets not only serves as a biomarker for acute coronary syndrome and acute ischemic stroke also actively participates in arterial thrombosis via its adhesive EGF-like repeats in vivo, suggesting that these adhesive motifs of SCUBE1 might serve as potential anti-thrombotic targets. However, when these SCUBEs expressed as peripheral membrane proteins tethered on the cell surface, they can function as co-receptor in promoting signal activity of various growth factors. We demonstrated that EC SCUBE2 acting as a co-receptor for vascular endothelial growth factor receptor 2 (VEGFR2) regulate VEGF-induced tube formation and proliferation of ECs: it fine-tunes VEGFR2-mediated signaling during postnatal angiogenesis induced by ischemia or during pathological angiogenesis under hypoxic conditions. Together, our studies suggest that targeting SCUBE2 on modulating VEGF signaling might provide potential therapeutic treatment for VEGF-mediated proliferative pathological vascular diseases. Most interestingly, we identified that bi-allelic inactivating variants in SCUBE3 have pleiotropic consequences on development and cause a previously unrecognized syndromic disorder. Eighteen affected individuals from nine unrelated families showed a consistent phenotype characterized by reduced growth, skeletal features, distinctive craniofacial appearance, and dental anomalies. In the future, we will continue to explore their in-depth fundamental biology by the use of genetically-modified mouse models as well as elucidate their translational implications through collaboration with physician scientists in the field of cardiovascular medicine.
Signal peptide-CUB-EGF-like repeat-containing protein 1-promoted FLT3 signaling is critical for the initiation and maintenance of MLL-rearranged acute leukemiaHaematologica, Aug 25, 2022