Merlin, a multi-suppressor from cell membrane to the nucleus.

Recent evidence suggests that the neurofibromatosis type 2 (NF2) gene encoded protein merlin suppresses mitogenic signalling not only at the cell membrane but also in the nucleus. At the membrane, merlin inhibits signalling by integrins and tyrosine receptor kinases (RTKs) and the activation of downstream pathways, including the Ras/Raf/MEK/ERK, FAK/Src, PI3K/AKT, Rac/PAK/JNK, mTORC1, and Wnt/β-catenin pathways. In the nucleus, merlin suppresses the E3 ubiquitin ligase CRL4(DCAF1) to inhibit proliferation. Gene expression analysis suggested that CRL4(DCAF1) could also regulate the expression of integrins and RTKs. In this review, we explore the links between merlin function at the membrane and in the nucleus, and discuss the potential of targeting the master regulator CRL4 (DCAF1) to treat NF2 and other merlin-deficient tumours.