Molecular characterization of protein kinase and transcription factor oncogenic gene fusions

Abstract

Cancer is characterized by a variety of genetic alterations including missense, nonsense, frameshift mutations, and chromosomal rearrangements. Chromosomal translocations often lead to oncogenic gene fusions, or oncofusions (OFs). A recent systems-level study concluded that protein kinases (PKs) and transcription factors (TFs) are the two main gene families producing in-frame fusions resulting into fusion proteins. The aim of my research was to study the interaction and functional landscape of a few representative fusion proteins with PK and TF as each other’s fusion partners.

Protein-protein interactions (PPIs) are crucial in disease networks and PPI investigation can reveal the underlying disease progression mechanism. We used proximity labeling and affinity purification coupled with liquid chromatography and mass spectrometry to capture and analyze both stable and transient interactors of fusion proteins.

It had been previously hypothesized that fusion proteins deregulate cellular signalling by acquiring novel functions while losing most of their parent protein functions. Our results establish that fusion proteins indeed interact with several unique interactors and are most often distributed in different cellular locations in comparison to their parent proteins. The results illustrate potential mechanisms via which fusion proteins can result in drastic changes in the biological functions of the affected cell population.