Related Experiment Video
Updated: Sep 28, 2026

Induction and Analysis of Epithelial to Mesenchymal Transition
Published on: August 27, 2013
AGK::BRAF fusion activates MAPK signaling, promotes genomic instability, and reduces NIS expression in thyroid cancer
Luiza Sisdelli1, Welbert Gomes Rocha1, Débora Mota Dias Thomaz1
1Genetic Basis of Thyroid Tumors Laboratory, Division of Genetics, Department of Morphology and Genetics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
Abstract:
The AGK::BRAF fusion is a recurrent oncogenic alteration in sporadic pediatric papillary thyroid carcinoma (PTC), frequently associated with multifocal disease and pulmonary metastasis. However, the molecular and cellular consequences of AGK::BRAF expression in thyroid follicular cells remain poorly defined. Here, we investigated the biological effects of AGK::BRAF in PCCL3 thyroid cells and compared them with those induced by clinically established pediatric PTC oncogenic drivers, including RET/PTC1, RET/PTC3, ETV6::NTRK3, BRAF V600E, and wild-type BRAF. AGK::BRAF-expressing cells exhibited the most robust MAPK/ERK activation, characterized by markedly enhanced ERK and MEK phosphorylation relative to all other oncogenic drivers analyzed. By contrast, STAT3 and AKT signaling remained comparatively modest and did not show consistent oncogene-specific activation patterns. Functionally, AGK::BRAF expression induced features of thyroid dedifferentiation, including reduced sodium-iodide symporter (NIS) expression and impaired iodide uptake. Concomitantly, AGK::BRAF-expressing cells exhibited increased frequencies of micronuclei and chromatin bridges, together with disruption of three-dimensional telomere architecture, including reduced telomere signal number and intensity, altered spatial organization, and increased nuclear volume. Three-dimensional structured illumination microscopy (3D-SIM) further demonstrated chromatin remodeling, characterized by increased chromatin condensation accompanied by enlarged interchromatin spaces. Collectively, these findings suggest that AGK::BRAF is a dominant oncogenic driver of sustained MAPK/ERK signaling coupled to thyroid dedifferentiation, nuclear architectural remodeling, telomere dysfunction, and genomic instability. These coordinated molecular and structural alterations provide a mechanistic basis for the aggressive clinical course observed in AGK::BRAF-driven pediatric PTC.
Related Concept Videos
MAPK Signaling Cascades
Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
NF-κB-dependent Signaling Pathway
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
Abnormal Proliferation
The Intrinsic Apoptotic Pathway
mTOR Signaling and Cancer Progression
The mTOR pathway or the...

