It is firmly established that Ras proteins are essential control elements of growth promoting signaling networks. Moreover, the deregulation of Ras signaling has been causally linked to a number of human malignancies. However, our understanding of molecular principles that govern the physiological and pathogenic activities of Ras proteins is still limited. The broad objective of this ongoing research program is to elucidate these principles and to determine how they are functionally linked to the control of cellular homeostasis. During the current funding period, we have described a previously unrecognized mechanism for the preferential partitioning of Ras proteins to the endocytic pathway which involves ubiquitin conjugation. Furthermore, we have shown that this targeting mechanism modulates Ras- dependent signaling. The goal of the studies proposed in the current application is to gain detailed knowledge of the regulation and functional consequences of Ras ubiquitination. We will exploit subcellular, cellular and organismal models to pursue the following aims: 1. To define the molecular machinery that controls Ras ubiquitination. Studies proposed within this aim are directed at the identification and characterization of the enzymes that mediate ubiquitin conjugation to and removal from Ras, as well as the delineation of the spatial regulation of Ras ubiquitination. 2. To establish the functional significance of Ras ubiquitination. Studies proposed within this aim are directed at testing the hypothesis that Ras signaling outcomes are influenced by Ras ubiquitination status both in physiological and pathological settings. Together, these studies will provide new insights into specification mechanisms that govern Ras signaling and may uncover new modalities for therapeutic intervention.
Cancer is among the leading cause of deaths in the United States. This project seeks to define fundamental mechanisms that promote the conversion of normal cells to cancer cells. It therefore, has the potential to lead to the identification of new anti-cancer therapeutic strategies.
|Grabocka, Elda; Commisso, Cosimo; Bar-Sagi, Dafna (2015) Molecular pathways: targeting the dependence of mutant RAS cancers on the DNA damage response. Clin Cancer Res 21:1243-7|
|Commisso, Cosimo; Flinn, Rory J; Bar-Sagi, Dafna (2014) Determining the macropinocytic index of cells through a quantitative image-based assay. Nat Protoc 9:182-92|
|Commisso, Cosimo; Davidson, Shawn M; Soydaner-Azeloglu, Rengin G et al. (2013) Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature 497:633-7|
|Pylayeva-Gupta, Yuliya; Grabocka, Elda; Bar-Sagi, Dafna (2011) RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer 11:761-74|
|Xu, Lizhong; Lubkov, Veronica; Taylor, Laura J et al. (2010) Feedback regulation of Ras signaling by Rabex-5-mediated ubiquitination. Curr Biol 20:1372-7|
|Lee, Kyoung Eun; Bar-Sagi, Dafna (2010) Oncogenic KRas suppresses inflammation-associated senescence of pancreatic ductal cells. Cancer Cell 18:448-58|
|Miaczynska, Marta; Bar-Sagi, Dafna (2010) Signaling endosomes: seeing is believing. Curr Opin Cell Biol 22:535-40|
|Fehrenbacher, Nicole; Bar-Sagi, Dafna; Philips, Mark (2009) Ras/MAPK signaling from endomembranes. Mol Oncol 3:297-307|
|Terrillon, Sonia; Bar-Sagi, Dafna (2008) Biochemical and biophysical analyses of Ras modification by ubiquitin. Methods Enzymol 438:259-76|
|Zhao, Chen; Du, Guangwei; Skowronek, Karl et al. (2007) Phospholipase D2-generated phosphatidic acid couples EGFR stimulation to Ras activation by Sos. Nat Cell Biol 9:706-12|
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