Changes in the cell microenvironment including oxygen availability, nutrient concentrations and the existence of the chemically active compounds may dramatically alter the cellular metabolism and signaling pathways. Such processes have been widely implicated in cancer initiation and proliferation. During these processes, cells activate specific signaling cascades through posttranslational modifications which eventually lead to the reprogramming of protein function that redefine the cellular landscape. Understanding the dynamics of these signaling events is critical to discover novel regulatory mechanisms and pathways that are functionally essential in these processes. We are applying the MS-based quantitative proteomics technology to systematically identify the temporal and spatial dynamics of the lysine methylation signaling networks in cancer cells in response to the environmental perturbations with an ultimate goal to reveal novel targets for therapeutic intervention of tumorigenesis and tumor progression.