POST-GOLGI SECRETION IN CELL GROWTH AND DIVISION

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。所有真核细胞的一个共同结构特征是一个复杂的膜网络，形成内部隔室，并确定细胞的边界。这些膜细胞器的形成和正常功能需要创造和维持其独特的蛋白质和脂质组成。这个过程，以及细胞生长和分裂所需的表面扩张，涉及高度调节的膜运输途径。细胞表面成分的传递通常是一个极化过程，使细胞形成专门的表面结构域。极化膜运输对于定向细胞生长和细胞运动也是必不可少的。此外，通过输出激素和神经递质等可溶性因子，通过调节细胞表面受体和转运体的传递和维持，膜交通途径提供了细胞与细胞外环境相互作用的手段，从而影响细胞分裂、形态发生和运动等过程。如果不能正确地调节这些过程，就会导致不受控制的细胞增殖和肿瘤的形成。因此，了解控制极化膜运输的机制对于了解癌症的发展至关重要。我们正在使用一个完善的酵母模型来进行经典和化学遗传筛选，以确定膜运输机制的新结构和调节成分。经典遗传筛选鉴定了一种新的保守蛋白av19，它与Rho3相互作用，Rho3是一种已知的极化分泌调节因子。消耗av19导致高尔基体分泌出口受阻。化学遗传策略已经确定了一组相关的化合物，导致分泌货物和高尔基膜的快速积累。部分分泌阻滞的突变体对这些化合物极度敏感。我们现在正在确定复合目标。这些结果证实了我们筛查策略的有效性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A common structural feature of all eukaryotic cells is an elaborate network of membranes that form internal compartments as well as define the boundary of the cell. The formation and proper functioning of these membrane organelles requires the creation and maintenance of their unique protein and lipid compositions. This process, as well as the surface expansion required for cell growth and division, involves highly regulated membrane trafficking pathways. Delivery of cell surface components is often a polarized process, enabling cells to form specialized surface domains. Polarized membrane transport is also essential for directed cell growth and cell motility. Furthermore, by exporting soluble factors such as hormones and neurotransmitters, and by regulating the delivery and maintenance of cell surface receptors and transporters, membrane traffic pathways offer a means by which cells interact with the extracellular environment, and thereby influence processes such as cell division, morphogenesis and motility. The failure to properly regulate these processes can lead to uncontrolled cell proliferation and tumor formation. Therefore, understanding the mechanisms that control polarized membrane transport is critical for understanding cancer development. We are using a well-established yeast model to conduct classical and chemical genetic screens for identifying novel structural and regulatory components of the membrane transport machinery. The classical genetic screen has identified a novel conserved protein, Avl9, which interacts with Rho3, a known regulator of polarized secretion. Depleting Avl9 results in a block of secretory exit from the Golgi. The chemical genetic strategy has identified a group of related compounds that cause a rapid accumulation of secretory cargo and Golgi membranes. Mutants with partial secretory blocks are hypersensitive to the compounds. We are now identifying compound targets. These results establish the effectiveness of our screening strategies.