Lung cancer is thought to develop in a stepwise fashion giving us the opportunity to intervene before it becomes invasive. A novel approach to cure patients of lung cancer is therefore to develop a targeted chemoprevention strategy to prevent the formation of lung premalignant lesions in the first place. My lab studies airway basal stem cells (ABSCs) and the signaling pathways involved in their repair and regeneration after injury. Our studies led us to the conclusion that premalignancy represents a state of excessive self-renewal of ABSCs with a block in differentiation and we identified several mechanisms involved in stepwise progression to Squamous Lung Cancer. One such mechanism involves proliferation of ABSCs via the Wnt-β-catenin pathway and in particular we found that only one of the differential phosphorylation sites, the tyrosine Y489 residue of the β-catenin protein, allowed nuclear localization of β-catenin with concomitant TCF/LEF activation for proliferation. We found that phosphorylation of other classically described β-catenin phosphorylation sites only resulted in membranous localization of β-catenin. The phosphorylation of β-catenin at Y489 (p-β-cateninY489) is not present in normal airway ABSCs and is turned on only briefly during normal repair after injury, but it persists in premalignant lesion ABSCs and in a subset of cells in Squamous Lung Cancer (SLC). Our goal is to understand the mechanisms that drive phosphorylation of β-catenin at Y489 and discover compounds to prevent this process. This will allow us to prevent the excessive proliferation of premalignancy and develop a novel chemoprevention strategy for SLC. We will achieve this goal with the following aims: Specific Aim 1: To understand the role of p-β-cateninY489 in proliferation of ABSCs, premalignant lesions and lung cancers. We hypothesize that p-β-cateninY489 is a common mechanism for proliferation in all histologic subtypes of lung cancer. Specific Aim 2: To identify the kinase/s responsible for phosphorylation of β-cateninY489 site in ABSCs. We hypothesize that there are specific kinase/s that phosphorylate β-catenin at the Y489 site which drives proliferation of ABSCs to form premalignant lesions. Specific Aim 3: To identify compounds that prevent p-β-cateninY489. We will perform a targeted screen of compounds that prevent TCF/LEF activation in ABSCs along with a toxicity screen. This will allow us to identify compounds that inhibit proliferation but are not toxic to ABSCs. Lead compounds from this primary screen will be taken to a secondary screen with immunofluorescence for p-β-cateninY489. Our highly accomplished research team, the outstanding environment at UCLA and the important biology that is being addressed in this proposal all provide a high likelihood that this NCI Provocative Question 1 will be answered for targeting premalignancy in Non-Small Cell Lung Cancer and lead to the development of a targeted chemoprevention strategy for Lung Cancer that will save millions of lives.