S-Space College of Natural Sciences (자연과학대학) Program in Genetic Engineering (협동과정-유전공학전공) Theses (Ph.D. / Sc.D._협동과정-유전공학전공)
Abl-Interactor (Abi) Regulation of BMP-Dependent Synaptic Growth through Macropinocytosis
Abl 상호작용 단백질인 Abi 에 의한 BMP 의존적 시냅스 성장 및 macropinocytosis 의 조절
- 자연과학대학 협동과정 유전공학전공
- Issue Date
- 서울대학교 대학원
- 학위논문 (박사)-- 서울대학교 대학원 : 자연과학대학 협동과정 유전공학전공, 2018. 2. 이승복.
- Glass bottom boat (Gbb), a bone morphogenetic protein (BMP) in Drosophila, is a key retrograde trans-synaptic signal required for normal synaptic development and function at the neuromuscular junction (NMJ). Although endocytosis appears to be a key mechanism to attenuate BMP signaling, the underlying mechanism remains elusive. Abi (Abl interactor) is a substrate adaptor protein for the Abl tyrosine kinase protein and a key component of the SCAR/WAVE protein complex, which relays signals from Rac to the Arp2/3 complex to regulate actin dynamics during macropinocytosis. Here, I provide evidence that Abi acts as a node of convergence of Abl- and Rac-mediated signaling to restrain BMP-dependent synaptic growth through macropinocytosis. Abi, Abl, and the Rac-SCAR/WAVE pathway regulate the growth of NMJ synapses via inhibition of BMP signaling. Genetic interactions indicate that Abi acts downstream of Abl and Rac to regulate synaptic growth. Gbb induces macropinocytosis in neurons and at the NMJ. Gbb-induced macropinocytosis critically depends on the Rac-SCAR/WAVE pathway and Abl-mediated phosphorylation of Abi, both of which are critical for the formation of F-actin-rich macropinocytic carriers. Importantly, macropinocytosis mediates Gbb-induced internalization of the BMP receptor Thickveins (Tkv) and is indispensable for its degradation. Finally, loss of other known regulators of macropinocytosis increases BMP signaling and synaptic growth at the NMJ. Based on these findings, I propose that Abi links Abl signaling with the Rac-SCAR/WAVE pathway to promote ligand-induced BMP receptor downregulation through macropinocytosis, thereby limiting this positive growth signal.