The T-box transcription factor, TBX3, is a key substrate of AKT3 in melanomagenesis
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Jade Peres1, Shaheen Mowla1, Sharon Prince1
1Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Observatory, 7925, Cape Town, South Africa
Sharon Prince, e-mail: [email protected]
Keywords: TBX3, AKT3, melanoma, E-cadherin, T-box factors
Received: September 12, 2014 Accepted: November 19, 2014 Published: December 16, 2014
The AKT3 signalling pathway plays a critical role in melanoma formation and invasion and components of this signalling cascade are therefore attractive targets for the treatment of malignant melanoma. Recent evidence show that the embryonically important TBX3 transcription factor is upregulated in a subset of melanomas and plays a key role in promoting melanoma formation and invasion, in part by repressing the cell adhesion molecule E-cadherin. We have identified TBX3 as a key substrate of AKT3 in melanomagenesis. Briefly, using site-directed mutagenesis and in vitro kinase assays, we have identified the AKT3 target site at serine residue 720 in the TBX3 protein and show that this site is phosphorylated in vivo. Importantly, we show by western blotting, immunofluorescence, reporter, migration and invasion assays that the phosphorylation at S720 promotes TBX3 protein stability, nuclear localization, transcriptional repression of E-cadherin, and its role in cell migration and invasion. Our results identify a novel signalling and transcriptional network linking AKT3, TBX3 and E-cadherin during melanoma migration and invasion and reveals TBX3 as a potential target for anti-metastatic therapeutics.
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