Merlin's tumor suppression linked to inhibition of the E3 ubiquitin ligase CRL4 (DCAF1)

Abstract

The mechanism by which the FERM domain protein Merlin, encoded by the tumor suppressor NF2, restrains cell proliferation is poorly understood. Prior studies have suggested that Merlin exerts its antimitogenic effect by interacting with multiple signaling proteins located at or close to the plasma membrane. We have recently observed that Merlin translocates into the nucleus and binds to and inhibits the E3 ubiquitin ligase CRL4 (DCAF1) . Genetic evidence indicates that inactivation of Merlin induces oncogenic gene expression, hyperproliferation, and tumorigenicity by unleashing the activity of CRL4 (DCAF1) . In addition to providing a potential explanation for the diverse effects that loss of Merlin exerts in multiple cell types, these findings suggest that compounds inhibiting CRL4 (DCAF1) may display therapeutic efficacy in Neurofibromatosis type 2 and other cancers driven by Merlin inactivation.

Figure 1

Merlin suppresses tumorigenesis by translocating into the nucleus and inhibiting the E3 ligase CRL4^DCAF1. Signals regulating cell growth from neighboring cells or extracellular matrix (ECM) regulate the phosphorylation status of Merlin through Pak. The active form of Merlin enters the nucleus and binds to the E3 ubiquitin ligase CRL4^DCAF1, thereby inhibiting its activity. Inset shows a model of the molecular architecture of the ligase. We posit that deregulated CRL4^DCAF1 drives the oncogenicity of Merlin-deficient cells by upregulating the expression of multiple oncogenic genes.