AEG-1/MTDH/LYRIC, the beginning: initial cloning, structure, expression profile, and regulation of expression

Abstract

Since its initial identification as a HIV-1-inducible gene in 2002, astrocyte elevated gene-1 (AEG-1), subsequently cloned as metadherin (MTDH) and lysine-rich CEACAM1 coisolated (LYRIC), has emerged over the past 10 years as an important oncogene providing a valuable prognostic marker in patients with various cancers. Recent studies demonstrate that AEG-1/MTDH/LYRIC is a pleiotropic protein that can localize in the cell membrane, cytoplasm, endoplasmic reticulum (ER), nucleus, and nucleolus, and contributes to diverse signaling pathways such as PI3K-AKT, NF-κB, MAPK, and Wnt. In addition to tumorigenesis, this multifunctional protein is implicated in various physiological and pathological processes including development, neurodegeneration, and inflammation. The present review focuses on the discovery of AEG-1/MTDH/LYRIC and conceptualizes areas of future direction for this intriguing gene. We begin by describing how AEG-1, MTDH, and LYRIC were initially identified by different research groups and then discuss AEG-1 structure, functions, localization, and evolution. We conclude with a discussion of the expression profile of AEG-1/MTDH/LYRIC in the context of cancer, neurological disorders, inflammation, and embryogenesis, and discuss how AEG-1/MTDH/LYRIC is regulated. This introductory discussion of AEG-1/MTDH/LYRIC will serve as the basis for the detailed discussions in other chapters of the unique properties of this intriguing molecule.

Keywords: AEG-1/MTDH/LYRIC; Cloning; HIV; Ha-ras; PI3K/AKT; c-Myc.

Figure 1.1

Sequence alignment and posttranslational modification of AEG-1/MTDH/LYRIC. Amino acid sequences of AEG-1/MTDH/LYRIC of seven representative vertebrates were aligned by ClustralW2 (http://www.ebi.ac.uk/Tools/services/web/toolform.ebi? tool=clustalw2) and curated with BOXSHADE 3.21 (http://www.ch.embnet.org/soft ware/BOX_form.html). Identities in the alignment are shown in inverted characters and similarities in shaded ones. Running PhosphoSitePlus (http://www.phosphosite.org/homeAction.do) identified 13 posttranslational modification sites (*, phosphorylation; u, ubiquitination; a, acetylation). Transmembrane domain (TMD), nuclear localization signals (NLS-1, 2, and 3), SND1/NF-κB-interacting domain (SND1/NF-κB), and lung-homing domain (LHD) are demarked by boxes. Unmarked sites here for legibility are PLZF-interacting domains (a.a. 1–285 and 487–582) and a BCCIP-interacting domain (a.a. 72–169) of human AEG-1/MTDH/LYRIC.

Figure 1.2

A Bayesian phylogenetic tree showing the relationships of vertebrate AEG-1/MTDH/LYRIC genes. The model used in the analysis was a GTR with invariants gamma. One million generations were run, upon which convergence of chains was assessed to be adequate. The tree is the result of removing a burn-in of 20%. All nodes in the tree except for those marked by blue circles have posterior probabilities of 0.99 or better. The nodes marked by blue circles had posterior probabilities between 0.5 and 0.8, suggesting that these nodes are not particularly robust. The different colored branches in the tree indicate well established taxonomic groups except for the dark blue which contains elephants and bats and horse. The more conventionally accepted groups are as follows: light blue, bony fish; purple, archosaurs and amphibians; light green, bovids and close relatives; red, carnivores; orange, rodents; black, primates. The inset table shows the base to tip distance of the indicated groups in the tree.

Figure 1.3

Molecular mechanism of AEG-1 function in HAD- and glioma-induced neurodegeneration. The EAAT2 in normal astrocytes is responsible for clearing extracellular glutamate to minimize excitotoxicity, and astrocytes convert glutamate to glutamine via the glutamine synthetase. Increased AEG-1 in HIV-infected astrocytes and glioma reduces EAAT2 expression and boosts synaptic glutamate concentrations. Increased synaptic glutamate overactivates glutamate receptors (GluRs), especially NMDA receptors (NMDARs) in postsynaptic neurons, resulting in induction of high levels of Ca²⁺ influx and apoptotic cell death.