The tumor suppressor protein PTEN undergoes amyloid-like aggregation in tumor cells.
Claes, F.; Maritschnegg, E.; De Baets, G.; Siekierska, A.; Saiz Rubio, M.; Ramakers, M.; Michiels, E.; De Smet, F.; Depreeuw, J.; Vergote, I.; Vanderstichele, A.; van den Broeck, A.; Olbrecht, S.; Hermans, E.; Amant, F.; Lambrechts, D.; Nilsson, P. R.; Rousseau, F.; Schymkowitz, J.
Show abstract
Protein aggregation is an underappreciated mechanism that may contribute to the loss- and oncogenic-gain-of-function of mutant tumor suppressors such as p53 and axin. In the present study, we describe amyloid-like aggregation behaviour of the second most frequently mutated tumor suppressor in human cancer, PTEN. In silico analysis revealed a particularly high aggregation vulnerability for this protein, which was corroborated by in vitro aggregation assays. In cultured tumor cells, we found that under stress conditions, PTEN readily undergoes amyloid-like aggregation as a result of mutation. However, we also show that severe dysregulation of protein homeostasis may lead to aggregation of wild-type PTEN. These observations were supported by a small survey of patient-derived uterine tumor tissues, which found that more than 25% of tumors analyzed displayed wild-type PTEN aggregation. Finally, in an exploratory clinical study we found that PTEN aggregation status was correlated with a decline in clinical outcome. Our findings establish that the tumor suppressor PTEN is highly aggregation-prone and our work suggests that protein aggregation might be an underestimated but prevalent component of cancer cell biology.
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