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.
本研究室致力於探討一個分泌性膜蛋白家族－－SCUBE (signal peptide-CUB-EGF domain-containing proteins) 於基礎與轉譯醫學上的重要性。此蛋白家族最初發現於內皮細胞中，共包括三個膜蛋白成員分別為SCUBE1、SCUBE2及SCUBE3，其在演化上高度保留，廣泛地存在於人類、小鼠與斑馬魚等脊椎動物體內。SCUBE因其表現於細胞之不同位置展現出其獨特的功能。例如，SCUBE1由活化態血小板分泌至血液中，藉由其具黏附特性之EGF重複序列 (EGF-like repeats) 促使血小板相互聚集與鏈結，為體內動脈血栓 (arterial thrombosis) 形成之重要機制。因此，SCUBE1不僅為急性冠狀動脈症候群 (acute coronary syndrome) 與急性缺血性腦中風 (acute ischemia stroke) 之生物標記，其具黏附特性之結構亦成為抗血栓藥物開發之標的。而當SCUBE蛋白以周膜蛋白 (peripheral membrane protein) 形式表現於細胞表面，其能作為輔受體 (co-receptor) 增強多種生長因子之訊號活性。我們的研究發現，內皮細胞表面之SCUBE2於缺血或缺氧環境中大量表現，並作為VEGFR2之輔受體，增強由VEGF誘發之內皮細胞生長速率與管腔生成 (tube formation)，於病理性血管新生 (pathological angiogenesis) 上扮演重要角色。因此，以SCUBE2為標靶或許為治療VEGF誘發之增生性血管病變之嶄新策略。此外，本研究團隊率先發現由SCUBE功能缺陷引發之發育障礙。來自9個國家彼此無血緣關係之18個個體，其SCUBE3基因產生雙等位基因失活變異體 (bi-allelic inactivating variants)，此變異體導致多重發育障礙綜合症，包括生長遲緩、骨骼異常、牙齒不規則排列並具有獨特的顱面外觀。未來，我們將通過與心血管醫學領域的醫生科學家合作，藉由基因修飾之小鼠模式以及由轉譯醫學的角度，持續深入探究SCUBE蛋白之生物功能。