Lung cancer is the leading cause of cancer mortality worldwide causing more than 1.3 million deaths each year. Over ~700,000 of these victims succumb to lung cancers that have alterations in one of the genes encoding members of the Ubiquilin family (UBQLN). The UBQLN family of proteins consists of 5 family members (UBQLN1-4 and UBQLNL), which all contain ubiquitin-like (UBL) and ubiquitin-associated domains (UBA). There is very limited data on biological processes regulated by UBQLN proteins. A direct role for UBQLN proteins in human cancer has not previously been examined. The goal of this proposal is to understand how disruption of UBQLN1 or UBQLN2 contributes to the metastatic progression of human lung adenocarcinoma. The ultimate goal of this project is to identify the cellular processes altered specifically in cancers that harbor loss of UBQLN function. The preliminary data in this proposal are the first to suggest that UBQLN loss is capable of directly altering processes involved in metastatic progression of human lung cancer. We demonstrate that loss of UBQLN1 or UBQLN2 increases EMT, migration, and invasion of transformed and non-transformed lung epithelial cells and that UBQLN1 regulates multiple pathways known to be critical in human lung cancer, including IGF1R, mTOR, MYC and ERK. We propose to examine, in detail, how UBQLN1 and UBQLN2 regulate key steps of metastatic progression in vitro, as well as determine if UBQLN1 loss alters the in vivo kinetics of metastatic tumor progression. Importantly, we have observed that one allele of UBQLN1 or UBQLN2 is lost in over 50% of human lung adenocarcinomas. The data gained from this application will determine if cancers harboring altered UBQLN function represent a novel subset of lung cancers and if the expression of UBQLN family members can be used as a predictive biomarker to determine which patients are more likely to succumb to metastatic lung cancer. By understanding how alterations in UBQLN1 signaling contributes to metastatic progression we may be able to target these downstream pathways specifically in tumors with altered UBQLN1 function to block metastasis, thus potentially affecting millions of lung cancer patients in the coming decades.