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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Salnikow, Konstantin
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
New York University
Schools of Medicine
New York
United States
Zip Code
Grabocka, Elda; Bar-Sagi, Dafna (2016) Mutant KRAS Enhances Tumor Cell Fitness by Upregulating Stress Granules. Cell 167:1803-1813.e12
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
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
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
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; 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; 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
Ochi, Atsuo; Nguyen, Andrew H; Bedrosian, Andrea S et al. (2012) MyD88 inhibition amplifies dendritic cell capacity to promote pancreatic carcinogenesis via Th2 cells. J Exp Med 209:1671-87
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

Showing the most recent 10 out of 58 publications