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Review
. 2014 Aug:27:39-45.
doi: 10.1016/j.semcancer.2014.06.003. Epub 2014 Jun 17.

Snail nuclear transport: the gateways regulating epithelial-to-mesenchymal transition?

Irfana Muqbil  1 , Jack Wu  1 , Amro Aboukameel  1 , Ramzi M Mohammad  2 , Asfar S Azmi  3
Affiliations
Review

Snail nuclear transport: the gateways regulating epithelial-to-mesenchymal transition?

Irfana Muqbil et al. Semin Cancer Biol. 2014 Aug.

Abstract

Epithelial-to-mesenchymal transition (EMT) and the reverse process (MET) play central role in organ developmental biology. It is a fine tuned process that when disturbed leads to pathological conditions especially cancers with aggressive and metastatic behavior. Snail is an oncogene that has been well established to be a promoter of EMT through direct repression of epithelial morphology promoter E-cadherin. It can function in the nucleus, in the cytosol and as discovered recently, extracellularly through secretory vesicular structures. The intracellular transport of snail has for long been shown to be regulated by the nuclear pore complex. One of the Karyopherins, importin alpha, mediates snail import, while exportin 1 (Xpo1) also known as chromosome maintenance region 1 (CRM1) is its major nuclear exporter. A number of additional biological regulators are emerging that directly modulate Snail stability by altering its subcellular localization. These observations indicate that targeting the nuclear transport machinery could be an important and as of yet, unexplored avenue for therapeutic intervention against the EMT processes in cancer. In parallel, a number of novel agents that disrupt nuclear transport have recently been discovered and are being explored for their anti-cancer effects in the early clinical settings. Through this review we provide insights on the mechanisms regulating snail subcellular localization and how this impacts EMT. We discuss strategies on how the nuclear transport function can be harnessed to rein in EMT through modulation of snail signaling.

Keywords: CRM1; EMT; Karyopherin; Nuclear transport; Xpo1.

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Figures

Figure 1
Figure 1. Snail structure
The N-terminal region [amino acid (aa) 1-150] of the Snail protein contains a SNAG (domain (aa 1-9) which includes the consensus sequence PRSFLV found in all Snail family members. This motif is highly conserved among species and also found in several other transcription factors where it is associated with repressive functions. The nuclear exporter Xpo5 recognizes SNAG domain and mediates SNAIL nuclear export. A serine-rich domain (SRD: aa 90-120) and a nuclear export sequence (NES: aa 139-148) are involved in the regulation of Snail protein stability and Xpo1/CRM1 mediated nuclear export, respectively. The C-terminal portion (aa 151-264) contains 3 typical (154-176, 178-202, 208-230) and one atypical (236-259) C2H2-type zinc finger (ZF) domains that serves as a NLS. A number of phosphorylation and ubiquitination sites exist on Snail that collectively regulates its turnover.
Figure 2
Figure 2. Snail Nuclear Import and Export a Mechanistic Summary
Snail Nuclear import and export are governed by evolutionary conserved nuclear transporters belonging to the Karyopherin family. An energy consuming process, Snail nuclear transport is mediated by nucleotide exchange factors RanGTP.
Figure 3
Figure 3. Snail Regulatory Mechanisms
Snail is highly labile protein that is rapidly degraded through proteasomal system. The F-box proteins (components of SCF ubiquitin-ligase complexes namely FBXL1 and FBXL14 enhance the nuclear export and induce ubiquitin-mediated proteolysis of Snail. FBXL5 induces nuclear ubiquitination of snail leading to its nuclear degradation. On the other hand phosphorylation by GSK3-β, PKA1, PDK1 and other can stabilize Snail and induce its nuclear retention.
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