Fig. 2: Tumour suppressor functions of BAP1, Merlin and p16^INK4a/p14^ARF proteins.

a In the endoplasmic reticulum (ER), BAP1 deubiquitinates and stabilises the type-3 inositol-1,4,5-trisphosphate receptor (IP3R3), controlling the Ca²⁺ flux into mitochondria and the subsequent release of cytochrome c and apoptosis. The nuclear BAP1 activity leads to BRCA1–BARD1-complex-dependent DNA repair as well as chromatin modification through histone deubiquitination. b At the plasma membrane, Merlin inhibits promigratory and prosurvival signalling cascades, including those mediated by focal adhesion kinase (FAK)–Src and phosphatidylinositol 3-kinase (PI3K)–AKT–mammalian target of rapamycin (mTOR)1 pathways. It also activates the mammalian Hippo pathway, which results in the phosphorylation of YAP/TAZ transcription co-activators, precluding their nuclear translocation and the TEA domain (TEAD)-dependent expression of numerous oncogenes. c p14^ARF promotes cell-cycle arrest and apoptosis by preventing p53 degradation, while p16^INK4a inhibits cell-cycle progression by binding and inactivating CDK4/6 protein and the downstream effector, retinoblastoma (Rb) protein.