Melanoma-associated loss-of-function mutations in protein phosphatase 6 cause dysregulation of Aurora-A

Proposed gain-of-function mutations in the PPP6C catalytic subunit of protein phosphatase 6 (PP6) act as drivers for the development of melanoma. Here we analyse primary melanoma and engineered cell lines and find that these melanoma-associated mutations in fact destabilize PPP6C due to increased turnover by the proteasome. Global analysis of phosphatase substrates by mass spectrometry reveals that the oncogenic kinase Aurora-A is dysregulated under these conditions. Accordingly, cells lacking PPP6C or carrying mutant PPP6C alleles have amplified Aurora-A kinase activity. This is noteworthy since gain-of-function mutation or amplification of Aurora-A promote a number of human cancers. Loss of PPP6C and associated amplification of Aurora-A activity result in chromosome instability, micronucleation and DNA damage; proposed initiators for chromothripsis. These data explain why loss of PP6 function is a driver for melanoma and provide a highly specific mechanism for the dysregulation and gain of Aurora-A activity in tumours.