Thyroid growth and differentiation are regulated by TSH via its receptor (TSHR), whilst growth factors signal in parallel via the MAPK/ERK and PI3K/AKT pathways. Aberrant thyroid growth is largely driven by molecular alterations within these signalling pathways. The proto-oncogene pituitary tumor-transforming gene-binding factor (PBF) is expressed in normal thyroid and upregulated in human goitre and thyroid cancer. High PBF expression is associated with tumour recurrence, distant metastasis and reduced survival in thyroid cancer. In experimental models, PBF induces goitre and tumours, and is pro-invasive. We recently demonstrated that phosphorylation of tyrosine residue 174 is mediated by the proto-oncogene protein tyrosine kinase Src. This prompted further investigation into a role for PBF in thyroid signalling pathways. PBF was phosphorylated in vivo in our mouse model of thyroid-specific PBF over-expression (PBF-Tg), accompanied by increased TSHR and cyclin D1 expression, and pAkt induction. In vitro studies showed that MAPK pathway stimulation with the BRAF V600E mutant, the most prevalent thyroid cancer mutation, results in increased PBF expression and phosphorylation, signifying a role for PBF in this critical thyroid signalling pathway. Epithelialmesenchymal transition (EMT) is a process by which cells lose cellcell contact, becoming migratory and invasive, and is governed by TGF-β, Runx2, Src and MAPK signalling in thyroid cancer. TGF-β treatment induced PBF phosphorylation, and Runx2 overexpression upregulated PBF expression in vitro. Importantly, reduced E-cadherin expression, a hallmark of EMT, was evident in the PBF-Tg mouse thyroid. We propose therefore that PBF is a component of the central thyroid signalling pathways that mediate normal thyroid growth and function, and that dysregulation of these pathways in nodular goitre and thyroid cancer induces PBF expression and phosphorylation. Further, we hypothesise that PBF may promote EMT-driven thyroid cancer progression, and is consequently both a negative prognostic factor and a putative therapeutic target for aggressive thyroid tumours.