Role of PTEN dysregulation downstream of ribosomal protein RPL5/RPL11 lesions in cancer.

We described that ribosomal protein L5 (RPL5) is heterozygously inactivated in 11-35% of samples from various tumor types and showed that 50% reduction of RPL5 levels accelerates tumor development. We now found that heterozygous RPL5 loss results in 20-40% downregulation of the tumor suppressor protein PTEN. RPL5 binds the PTEN protein, and also RPL11 is part of this complex. RPL11 is another haploinsufficient tumor suppressor for which 1 allele is lost in 10-30% of samples from various tumor types and 50% downregulation of RPL11 also reduces PTEN protein levels. RPL5 and RPL11 can regulate TP53 and MYC, but tumors with RPL5 inactivation do not show consistent TP53 or MYC dysregulation. Therefore, we hypothesize that PTEN downregulation is important for the tumor suppressive role of RPL5/RPL11. We will explore how RPL5 and RPL11 regulate PTEN and which PTEN functions are affected by heterozygous RPL5/RPL11 loss. Our data indicate that other PTEN roles besides the canonical PI3K-AKT-mTOR regulation are affected. Therefore, we will apply unbiased proteomics approaches to characterize the composition of the PTEN/RPL5/RPL11 complex and to identify phosphorylations that change due to PTEN downregulation upon RPL5/RPL11 loss. Finally, the importance of PTEN downregulation for the tumor suppressor function of RPL5 and RPL11 will be delineated. Results from this project will allow to identify the best drug targets to suppress RPL5 and RPL11 deficient cancers in follow-up projects.