Substantial experimental evidence now implicates a strong involvement of oncogenic human ras proteins in human carcinogenesis. Unexpectedly, the three human ras proteins represent only a small branch of a larger superfamily of ras-related proteins. Over the past several years, molecular, biochemical and genetic approaches have identified over 30 distinct members of the ras superfamily. The strong structural and biochemical similarities between ras and ras-related proteins suggest the possibility that they may also be candidates for oncogene proteins. The brisk pace at which new members have been identified suggests that the spectrum of ras-related proteins will be quite extensive, and their functions diverse. While ras is believed to be involved in signal transduction, these related proteins are likely to be involved in regulation of a diverse range of cellular functions in eukaryotic cells. In particular, the members of the rab protein branch are believed to be involved in the regulation of vesicular trafficking of protein through the endocytic and exocytic pathways of eukaryotic cells. Our interest in rab proteins is two-fold. First, we are interested in the study of rab proteins as naturally occurring, nontransforming variants of the ras oncogene proteins as an approach for defining the properties of ras proteins critical for oncogenesis. Second, we are interested in establishing a regulatory role for rab proteins in intracellular transport. We will use our extensive knowledge of ras protein structure and biochemistry as a strong foundation to characterize the structural, biochemical, and functional properties of rab proteins.
The specific aims of this proposal are (1) to determine the structural and biochemical properties of rab proteins which distinguish them from the ras oncogene proteins, (2) to determine the posttranslational modifications and amino acid sequences that determine the unique subcellular localization of each rab protein, (3) to evaluate the role of rab proteins in regulating intracellular transport processes, and (4) to determine whether rab proteins are potential oncogene proteins, or alternatively, can function to antagonize ras transforming function. This last aim will also address the role of the unique rab and ras subcellular associations in determining their unique functions. The observations that both exocytic and endocytic events are triggered by ras proteins suggest functional similarities between ras and rab proteins, and suggest that aberrant forms of rab may perturb transport processes thereby contributing to malignant growth potential. Since intracellular transport processes are fundamental to the maintenance of cell homeostasis, disruptions in these functions may exert profound effects on intracellular processes controlling cell proliferation. The information from our studies will both provide a better understanding of ras oncogene function and extend our understanding of the involvement of related GTP-binding regulatory proteins in cellular processes such as signal transduction and intracellular transport.
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