Yin6, a fission yeast Int6 homolog, complexes with Moe1 and plays a role in chromosome segregation

The INT6 gene has been implicated in human breast cancer formation, but its function is unknown. We isolated an Int6 homolog from fission yeast, Yin6, by its binding to a conserved protein in the Ras pathway, Moe1. Yin6 and Moe1 converge on the same protein complex to promote microtubule instability/disassembly. Yin6 and Moe1 interact cooperatively: when either protein is absent, the other becomes mislocalized with decreased protein levels. Furthermore, whereas full-length human Int6 rescues the phenotypes of the yin6-null (yin6Δ) mutant cells and binds human Moe1, truncated Int6 proteins found in tumors do not. Importantly, yin6Δ alone impairs chromosome segregation weakly, but yin6Δ together with ras1Δ causes severe chromosome missegregation. These data support a model in which INT6 mutations in humans either alone or together with additional mutations, such as a RAS mutation, may contribute to tumorigenesis by altering genome stability.