The cellular signaling circuitry has many types of regulation, from transcriptional control to regulation of protein degradation. These processes are often modulated by enzymatic modification of the proteins involved, and thus the modification of proteins is an integral part of most signal transduction pathways. In this project we plan to develop methods for detecting modifications within the proteome. Our initial focus will be on detecting tyrosine phosphorylation of proteins in cancer. We plan to develop methods for enriching cellular extracts for modified proteins directly coupled to methods for mass spectrometry-based detection and identification of these proteins. We also plan to demonstrate the usefulness of these """"""""modification profiling"""""""" techniques by applying them to the study of specific biological questions. Misregulated tyrosine phosphorylation is a characteristic of many types of cancer, and several successful anticancer therapies are designed to inhibit activated tyrosine kinases associated with particular cancers. Thus, knowledge of additional examples of tyrosine kinase activities linked to cancer can ultimately be translated into new clinical therapies. This project will initially allow for the scholarly development of the candidate under the mentorship of the sponsor Dr. David Eisenberg, and the collaborators Dr. Joseph Loo and Dr. Charles Sawyers, and will ultimately result in an independent research project. The methods for collecting protein modification data to be developed in this project will complement existing methods for measuring gene expression data, assisting in one of the fundamental goals of genomics and proteomics - to understand the circuitry of the cell.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Career Transition Award (K22)
Project #
1K22HG002807-01
Application #
6605137
Study Section
Ethical, Legal, Social Implications Review Committee (GNOM)
Program Officer
Felsenfeld, Adam
Project Start
2003-05-12
Project End
2008-03-31
Budget Start
2003-05-12
Budget End
2004-03-31
Support Year
1
Fiscal Year
2003
Total Cost
$146,526
Indirect Cost
Name
University of California Los Angeles
Department
Genetics
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Zimman, Alejandro; Berliner, Judith A; Graeber, Thomas G (2013) Phosphoproteomic analysis of aortic endothelial cells activated by oxidized phospholipids. Methods Mol Biol 1000:53-69
Rubbi, Liudmilla; Titz, Björn; Brown, Lauren et al. (2011) Global phosphoproteomics reveals crosstalk between Bcr-Abl and negative feedback mechanisms controlling Src signaling. Sci Signal 4:ra18
Fang, Cong; Wang, Yanju; Vu, Nam T et al. (2010) Integrated microfluidic and imaging platform for a kinase activity radioassay to analyze minute patient cancer samples. Cancer Res 70:8299-308
Graeber, T G; Heath, J R; Skaggs, B J et al. (2010) Maximal entropy inference of oncogenicity from phosphorylation signaling. Proc Natl Acad Sci U S A 107:6112-7
Zimman, Alejandro; Chen, Sharon S; Komisopoulou, Evangelia et al. (2010) Activation of aortic endothelial cells by oxidized phospholipids: a phosphoproteomic analysis. J Proteome Res 9:2812-24
Titz, B; Low, T; Komisopoulou, E et al. (2010) The proximal signaling network of the BCR-ABL1 oncogene shows a modular organization. Oncogene 29:5895-910
Zimman, Alejandro; Mouillesseaux, Kevin P; Le, Thang et al. (2007) Vascular endothelial growth factor receptor 2 plays a role in the activation of aortic endothelial cells by oxidized phospholipids. Arterioscler Thromb Vasc Biol 27:332-8