The overall goal of this Program Project is to understand the molecular mechanisms involved in signal transduction during membrane trafficking and cell proliferation. Interest is focused on the role of receptor tyrosine kinases, small GTP-binding proteins, heterotrimeric G proteins, and their upstream and downstream effectors. Project 1: The goal of this project is to determine the role of G protein-mediated signaling pathways in the control of Golgi organization and vesicular trafficking to and through the Golgi apparatus. Emphasis will be on determining the role of GAIP and other RGS proteins in these processes. Project 2: This project will establish the morphological basis for the regulation of ER to Golgi transport by small GTPases. Specific goals are to establish the role of Sar1 GTPase in assembly of COPII coats and the role of ARF1 of the genetic approach and availability of mutants defective in specific steps in vacuolar (lysosomal) targeting in yeast to identify proteins important in targeting. Three such mutants to be investigated have defective genes whose products share sequence homology with a phosphatidylinositol 3- kinase similar to those that associate with growth factor receptors, a Ser/Thr protein kinase and a rab GTPase. Project 4: The purpose of this project is to define the sequence codes of sorting, down-regulation and recycling of the EGF receptor. Specific goals are to determine the role of SNX1 in trafficking to endosomes and lysosomes and to identify the sequence codes in the EGF receptor required for sorting of the transferrin receptor from the EGF receptor. Project 5: The goal of this project is to investigate the molecular mechanisms of tyrosine kinase signaling during endocytosis. EGF receptor signaling cascades will be analyzed in rab 5 and rab 7 mutants with defects in endocytic trafficking. A detailed morphological and biochemical analysis will also be carried out on the interactions of SH2 domain proteins with activated EGF receptors. Project 6: This project focuses on analyzing the glycosylation machinery in individual Golgi subcompartments of normal and transformed cells focusing on early stages in the biosynthesis of lysosomal enzymes and on 9-0- acetylation of sialic acid. An Administration Core (Core A), an Immunocytochemistry Core (Core B) and a Live Cell Imaging Core (Core C) will provide support for the projects.
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