Signal transduction is a fundamental process that enables cells to acquire information from the extracellular environment and respond to this information appropriately. Molecular defects in this process are now recognized as a leading cause of a host of human diseases. Receptor tyrosine kinases (RTKs) are key mediators of signal transmission in response to extracellular cues that regulate cell proliferation and differentiation. It is widely accepted that differences in the duration and intensity of RTK-dependent signals constitute important determinants in dictating the nature of the biological response they elicit. However, relatively little is known about the regulatory principles that govern the quantitative output of signals generated in response to RTK activation. This application is motivated by the need to elucidate these principles with precision and to understand how they contribute to the signaling repertoire of RTKs at the cellular level. To accomplish this objective, the proposed studies will focus on the positive and negative modulation of the EGFR-Ras signaling axis by Son of sevenless (Sos) and Spry (Spry), respectively. The experimental plans consist of two broad aims: (1) To define the molecular framework for Sos-dependent coupling of EGFR to Ras activation. (2) To determine the functional interface between Spry and EGFR signaling. These investigations should advance our understanding of fundamental mechanisms that control the response capabilities of RTK signaling pathways and provide insights into molecular determinants that contribute to human disease.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Membrane Biology and Protein Processing (MBPP)
Program Officer
Gindhart, Joseph G
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
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
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
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
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
Pylayeva-Gupta, Yuliya; Grabocka, Elda; Bar-Sagi, Dafna (2011) RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer 11:761-74

Showing the most recent 10 out of 14 publications