Summary (30 lines) Our research program aims to understand how cells control intracellular signaling to respond and adapt to their environments. We will focus on three processes: Project 1 will examine the chemotactic migration of cells in extracellular chemical gradients, Project 2 will look at DNA repair after oxidative, genotoxic, and mechanical stress, and Project 3 will investigate the reprogramming of cell proliferation signaling in response to receptor tyrosine kinase inhibition. Project 1: GTPases are crucial for signal transduction in many cellular activities. Recently, we discovered an unforeseen, evolutionarily conserved mechanism by which GDP-bound Rho GTPase activates mTORC2, a critical serine/threonine kinase, in Dictyostelium and human cells. We will investigate the fundamental mechanism underlying this novel regulation of small GTPases using the robust chemotactic signaling in Dictyostelium cells as a discovery tool supported by an array of cutting-edge technologies. Successful outcomes will broadly impact tissue development, wound healing, neuronal wiring, and immune responses, as chemotaxis is crucial for these essential processes. Project 2: PTEN protects the genome from stress in the nucleus. PTEN accumulates in the nucleus upon stress via ubiquitin signaling. Identifying the ubiquitin ligase that controls PTEN after stress represents a critical knowledge gap in our understanding of PTEN's stress signaling. Using a genome-wide CRISPR screen, we will comprehensively test the function of E3 ligases under various forms of stress, such as oxidative, genotoxic, and mechanical stress. We will subsequently investigate how stress regulates the ubiquitin ligases. Project 3: Cells can adapt to unfavorable surroundings and weakened physiology by rearranging signal transduction pathways. We will analyze how cells alter signaling networks when the activity of vital signaling components is inhibited using innovative approaches, including AI-based multiplexed biosensor barcoding. We focus on the EGF receptor, which is essential for physiology and development. Outcomes will reveal the basic mechanisms by which cells can rewire signal transduction pathways and bypass the inhibition of essential signaling elements.