Epithelial protein lost in neoplasm (EPLIN)-beta is a novel substrate of ornithine decarboxylase antizyme 1, mediating cellular migration

Abstract

Polyamines promote cellular proliferation, and their levels are controlled by ornithine decarboxylase antizyme 1 (Az1), through the proteasome-mediated, ubiquitin-independent degradation of ornithine decarboxylase (ODC), the rate-limiting enzyme of polyamine biosynthesis. Az1-mediated degradation of other substrates such as cyclin D1, DNp73 and Mps1 also regulate cellular migration and centrosome amplification, and collectively, the currently known six Az1-substrates are all linked with tumorigenesis. To understand if Az1-mediated protein degradation might play a key role in regulating cellular process associated with tumorigenesis, we employed quantitative proteomics to identify novel Az1 substrates. In this report, we describe the identification of LIM domain and Actin-binding protein 1 (LIMA1), also known as epithelial protein lost in neoplasm (EPLIN), as a new target of Az1. Interestingly, between the two isoforms of EPLIN ( and {beta}), only EPLIN-{beta} is the substrate of Az1, degraded in a proteasome-dependent and ubiquitination-independent manner. Absence of Az1 led to elevated EPLIN-{beta} levels, which is causal to enhanced cellular migration of Az1-/- cells. Consistently, higher levels of LIMA1 expression correlated with poorer overall survival of colorectal cancer patients. Taken together, this study identifies EPLIN-{beta} as a novel Az1 substrate that regulates cellular migration.