Receptor tyrosine kinases (RTK) are essential mediators of signal transmission in response to extracellular cues that regulate fundamental processes such as cell proliferation, differentiation and survival. A central route by which RTK-initiated signals are transduced involves the activation of the small guanine nucleotide binding protein Ras. Activated Ras in turn induces a broad spectrum of cellular responses through the stimulation of multiple effector pathways. There is now ample genetic and biochemical evidence indicating that changes in the duration and intensity of intracellular signals elicited by the RTK-Ras pathway can lead to profound alterations in the biological outcome. Moreover, deregulated RTK-Ras signaling has been causally linked to a number of human malignancies and developmental disorders. The broad objective of this project is to define regulatory principles that govern the quantitative output of RTK-Ras signaling. The proposed studies will focus on the interaction between Ras and its guanine nucleotide exchange factor Sos as this interaction constitutes the rate limiting step in signal propagation from RTK to Ras. Our own work carried out for over a decade, as well as studies by other groups have indicated that Sos function is controlled through a complex network of inter- and intra-molecular interactions. Experiments described in this application are designed to further our understanding of the identity and functional significance of these interactions. We will undertake a multipronged strategy consisting of state-of-the-art biochemical and cell biological approaches to achieve four specific goals: (1) To establish the spatio-temporal dynamics of Sos-mediated Ras activation (2) To define how Sos-mediated Ras activation is terminated (3) To determine the role of Sos in Ras-driven tumors (4) To develop inhibitors of Ras-Sos interactions The information gathered from these studies should therefore furnish new insights into the regulatory paradigms that account for appropriate cellular adaptation in response to RTK-Ras signaling as well as the adverse consequences of deregulated RTK-Ras signaling.
The activation of Ras by receptor tyrosine kinases constitutes an essential step in the process that enables cells to acquire information from the extracellular environment and respond to this information appropriately. This application focuses on the mechanisms that regulate this step. Experiments proposed herein should thus advance our understanding of the link between signal transduction processes and cellular adaptation and provide insights into signaling defects that underlie a host of human diseases.
| Christensen, Sune M; Tu, Hsiung-Lin; Jun, Jesse E et al. (2016) One-way membrane trafficking of SOS in receptor-triggered Ras activation. Nat Struct Mol Biol 23:838-46 |
| 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 |
| 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 |
| 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 |
| Zheng, Ze-Yi; Xu, Lizhong; Bar-Sagi, Dafna et al. (2012) Escorting Ras. Small GTPases 3:236-9 |
| Jeng, Hao-Hsuan; Taylor, Laura J; Bar-Sagi, Dafna (2012) Sos-mediated cross-activation of wild-type Ras by oncogenic Ras is essential for tumorigenesis. Nat Commun 3:1168 |
| 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 |
| Pylayeva-Gupta, Yuliya; Grabocka, Elda; Bar-Sagi, Dafna (2011) RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer 11:761-74 |
| Patgiri, Anupam; Yadav, Kamlesh K; Arora, Paramjit S et al. (2011) An orthosteric inhibitor of the Ras-Sos interaction. Nat Chem Biol 7:585-7 |
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