A new mechanism of BRAF activation in human thyroid papillary carcinomas

Abstract

In this issue of the JCI, Ciampi et al. report the identification of a novel oncogene in patients affected by radiation-associated thyroid papillary carcinomas. This oncogene derives from a paracentric inversion of the long arm of chromosome 7, which results in an in-frame fusion of the N-terminus of the A-kinase anchor protein 9 (AKAP9) gene with the C-terminal catalytic domain (exons 9-18) of the serine-threonine kinase BRAF. The resulting AKAP9-BRAF fusion protein shows constitutive kinase activity, and it is able to transmit mitogenic signals to the MAPK pathways and to promote malignant transformation of NIH3T3 cells.

Figure 1

Molecular mechanism of the chromosomal rearrangement generating the transforming AKAP9-BRAF oncogene in PTCs.

Figure 2

The MAPK pathway. Once activated, tyrosine kinase (TK) receptors activate the monomeric G protein RAS (pathway I), which in turn binds the serine-threonine kinase BRAF by inducing a conformational change that allows its activation (pathway I) and hence activation of the MAPK pathway. The activation of the MAPK pathway results in DNA synthesis in response to the external mitogenic stimulus (pathway I). When the RET/PTC (pathway II) or the BRAF (pathway II) oncogenes are generated through chromosomal rearrangements, activation of the MAPK pathway becomes constitutive, and cells become able to proliferate indefinitely, to grow in an anchorage-independent manner, and to induce tumors after injection into athymic mice (pathway II). MEK, MAPK/ERK kinase; L, ligand.