The overall hypothesis of this proposal is that Ubiquilin1 suppresses critical signaling pathways that drive the pathogenesis of both Alzheimer's disease and cancer. These two diseases represent two of the largest burdens on the healthcare systems in all developed countries. In the U.S. the annual national expenditure for these two diseases combined is ~$300 billion dollars. Currently in the U.S. there are ~5.4 million people living with Alzheimer's disease and there will be ~1.7 million new cancer cases diagnosed this year. Only by understanding the basic molecular, biochemical and genetic causes of these diseases will we be able to make significant progress in treating these patients. Interestingly, it has been reported, but largely ignored, that there are common signaling pathways that are altered to drive the onset of both Alzheimer's disease and cancer. This proposal seeks to understand how the of scaffold protein, Ubiquilin1, regulates seemingly opposing cellular outcomes in epithelial cells and neuronal cells. Loss of Ubiquilin1 in epithelial cells increases proliferation and migration, whereas in neuronal cells, it causes cell death. Amazingly, there are a number of additional signaling pathways that behave in a similar cell-type and context-dependent manner, including amyloid precursor protein (APP), growth factor receptors (such as IGF1R) and focal adhesion complexes, such that aberrant activation of processes contributes to both tumorigenic phenotypes, as well as progression of Alzheimer's disease. We are the first to show that loss of Ubiquilin1, as seen in cancer and Alzheimer's disease, causes increased growth factor receptor signaling and increased focal adhesion formation and signaling. In this proposal we will examine the detailed molecular and biochemical regulation of these processes by Ubiquilin1 and we will examine the cell-type and context-dependent differences of Ubiquilin1 function in epithelial and neuronal cells. This information will shed light on the basic mechanisms that contribute to multiple diseases afflicting millions of people every year.

Public Health Relevance

Alzheimer's disease and cancer are seemingly caused by contrasting cellular processes; aberrant cell death for Alzheimer's disease and aberrant cell survival for cancer. The family of adapter proteins, Ubiquilins, are lost in both cancer and in Alzheimer's disease. The goal of this proposal is to determine how Ubiquilin proteins normally function to keep epithelial cells from aberrantly proliferating, while keeping neuronal cells from dying.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Ault, Grace S
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Louisville
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Barve, Aditya; Casson, Lavona; Krem, Maxwell et al. (2018) Comparative utility of NRG and NRGS mice for the study of normal hematopoiesis, leukemogenesis, and therapeutic response. Exp Hematol 67:18-31
Shah, Parag P; Dupre, Tess V; Siskind, Leah J et al. (2017) Common cytotoxic chemotherapeutics induce epithelial-mesenchymal transition (EMT) downstream of ER stress. Oncotarget 8:22625-22639
Kurlawala, Zimple; Dunaway, Rain; Shah, Parag P et al. (2017) Regulation of insulin-like growth factor receptors by Ubiquilin1. Biochem J 474:4105-4118
Yadav, Sanjay; Singh, Nishant; Shah, Parag P et al. (2017) MIR155 Regulation of Ubiquilin1 and Ubiquilin2: Implications in Cellular Protection and Tumorigenesis. Neoplasia 19:321-332
Kurlawala, Zimple; Shah, Parag P; Shah, Charmi et al. (2017) The STI and UBA Domains of UBQLN1 Are Critical Determinants of Substrate Interaction and Proteostasis. J Cell Biochem 118:2261-2270
Scherzer, Michael T; Waigel, Sabine; Donninger, Howard et al. (2015) Fibroblast-Derived Extracellular Matrices: An Alternative Cell Culture System That Increases Metastatic Cellular Properties. PLoS One 10:e0138065