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.
|Kamphorst, Jurre J; Nofal, Michel; Commisso, Cosimo et al. (2015) Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. Cancer Res 75:544-53|
|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|
|Grabocka, Elda; Pylayeva-Gupta, Yuliya; Jones, Mathew J K et al. (2014) Wild-type H- and N-Ras promote mutant K-Ras-driven tumorigenesis by modulating the DNA damage response. Cancer Cell 25:243-56|
|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|
|Pylayeva-Gupta, Yuliya; Lee, Kyoung Eun; Bar-Sagi, Dafna (2013) Microdissection and culture of murine pancreatic ductal epithelial cells. Methods Mol Biol 980:267-79|
|Court, Helen; Amoyel, Marc; Hackman, Michael et al. (2013) Isoprenylcysteine carboxylmethyltransferase deficiency exacerbates KRAS-driven pancreatic neoplasia via Notch suppression. J Clin Invest 123:4681-94|
|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; Lee, Kyoung Eun; Hajdu, Cristina H et al. (2012) Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell 21:836-47|
|Mallen-St Clair, Jon; Soydaner-Azeloglu, Rengin; Lee, Kyoung Eun et al. (2012) EZH2 couples pancreatic regeneration to neoplastic progression. Genes Dev 26:439-44|
|Yang, Moon Hee; Nickerson, Seth; Kim, Eric T et al. (2012) Regulation of RAS oncogenicity by acetylation. Proc Natl Acad Sci U S A 109:10843-8|
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