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Basic Research

Tyrosine Phosphorylation and the Phosphoproteome

The human genome encodes approximately 90 protein tyrosine kinases (PTKs), including both cytoplasmic tyrosine kinases (CTKs) and receptor tyrosine kinases (RTKs), that play a critical role in cell proliferation, differentiation, motility, and apoptosis. Because aberrant tyrosine kinase activation is a main driving force in many cancers, tyrosine kinases are important and proven therapeutic targets. A PTK functions by phosphorylating specific Tyr residues on a substrate, which, in turn, alters the structure, localization or interaction for that substrate. An early step in PTK signaling involves the binding of Src homology 2 or SH2 domain-containing proteins to specific Tyr phosphorylation sites. An important focus in my lab is to decipher the specificity of the 120 SH2 domains encoded by the human genome and the underlying structural basis. Another thrust of our research is to systematically identify tyrosine phosphorylation and the pTyr-mediated protein-protein interaction network in normal and cancer cells or tissues using proteomic techniques such as mass spectrometry and peptide and protein arrays.

Protein Methylation and the Lysine Methylome

Methylation of Lys and Arg residues has emerged as a prevalent post-translational modification (PTM) occurring on numerous non-histone proteins, thereby drastically extending its role beyond the histone code. We have developed an approach that combines mass spectrometry with peptide arrays and bioinformatics to systematically identify Lys methylation and quantify dynamic changes in the methylproteome associated with tumorigenesis or drug resistance. Our studies to date not only led to the identification of numerous novel methylation sites, but also generated new insights into how protein methylation regulates cellular functions such as the DNA damage repair, apoptosis and drug resistance. With recent advances in mass spectrometry and related proteomic techniques, the stage is now set to decode the methylproteome and to define it functions in health and disease.