AKT-ions with a TWIST between EMT and MET

Abstract

The transcription factor Twist is an important regulator of cranial suture during embryogenesis. Closure of the neural tube is achieved via Twist-triggered cellular transition from an epithelial to mesenchymal phenotype, a process known as epithelial-mesenchymal transition (EMT), characterized by a remarkable increase in cell motility. In the absence of Twist activity, EMT and associated phenotypic changes in cell morphology and motility can also be induced, albeit moderately, by other transcription factor families, including Snail and Zeb. Aberrant EMT triggered by Twist in human mammary tumour cells was first reported to drive metastasis to the lung in a metastatic breast cancer model. Subsequent analysis of many types of carcinoma demonstrated overexpression of these unique EMT transcription factors, which statistically correlated with worse outcome, indicating their potential as biomarkers in the clinic. However, the mechanisms underlying their activation remain unclear. Interestingly, increasing evidence indicates they are selectively activated by distinct intracellular kinases, thereby acting as downstream effectors facilitating transduction of cytoplasmic signals into nucleus and reprogramming EMT and mesenchymal-epithelial transition (MET) transcription to control cell plasticity. Understanding these relationships and emerging data indicating differential phosphorylation of Twist leads to complex and even paradoxical functionalities, will be vital to unlocking their potential in clinical settings.

Keywords: Akt; Twist; epithelial-mesenchymal transition; phosphorylation; plasticity.

Figure 1. Plastic epithelial-to-mesenchymal transition

Transcriptional regulation of EMT by activated Twist, Snail and Zeb oncogenic proteins is often accompanied with cellular morphological change. EMT: epithelial-mesenchymal transition; MET: mesenchymal-epithelial transition. Red: high level; blue: low level.

Figure 2. Twist structure and phosphorylation conservation in mammals

Twist has three major domains including a N-terminal flexible domain, a basic helix-loop-helix domain that is responsible for DNA-binding and a C-terminal Twist-box. Differential phosphorylation patterns that have been reported are indicated. In mammals there are two members in Twist family. The phosphorylated amino acids highlighted in red are highly conserved in both members across three species (m: mouse; r: rat; h: human). CK2: casein kinase 2; bHLH: basic helix-loop-helix; T-box: Twist-box.

Figure 3. Upstream and downstream regulation of Twist

At transcriptional level, NF-κB, STAT3, DLX4, MYCN, MYC, HMGA2 and SOX2 have been shown to upregulate Twist in response to the activation of TGFbeta, RTKs, WNT and Integrin pathways. Being a central hub, translated Twist undergoes differential phosphorylation directly mediated by Akt, MAPK and CK2 kinases in a context-dependent manner. Activation of Twist via phosphorylation triggers oncogenic gene expression such as AKT, TGFB and PDGFR, and represses E-cadherin (CDH1), Claudins (CLDN), Raf kinase inhibitor protein (RKIP) and Nephrin1 (NPHS1) that are crucial for cell-cell contact through its downstream target Snail, an epigenetic event that actively leads to an reinfoced EMT activation. PTM: post-translational modification.