VprBP targets Merlin to the Roc1-Cul4A-DDB1 E3 ligase complex for degradation

Abstract

Inactivation of the neurofibromatosis type 2 (NF2) tumor suppressor gene function has been observed not only in familial schwannomas and other central nervous system tumors, but also in malignant tumors unrelated to the NF2 syndrome, indicating a broader role of NF2 in human tumorigenesis. The NF2-encoded protein Merlin is closely related to the Ezrin-Radixin-Moesin family of membrane/ cytoskeleton linker proteins, and has been demonstrated to suppress tumor growth by inhibiting extracellular signal-regulated kinase (ERK) and Rac1 activation. Interestingly, serum deprivation has been shown to regulate Merlin at the protein level, however, exactly how such condition affects Merlin remains elusive. In this study, we provide evidence to show that Merlin is regulated in a Roc1-Cullin4A-DDB1-dependent manner. Following serum stimulation, Merlin is recruited to the E3 ligase complex through a direct interaction with the WD40-containing adaptor protein VprBP. Loading of Merlin to the E3 ubiquitin ligase complex resulted in its polyubiquitination, and consequently its proteasomemediated degradation. Consistently, VprBP depletion abolished the in vivo interaction of Merlin and Roc1-Cullin4A-DDB1, which resulted in Merlin stabilization and inhibited ERK and Rac activation. Together, our data revealed a novel regulatory mechanism for the tumor suppressor function of Merlin.

Vpr-Binding Protein Antagonizes p53-Mediated Transcription via Direct Interaction with H3 Tail

“…VprBP is a 1,507-amino-acid protein that contains conserved domains, including YXXY repeats, the Lis homology motif, and WD40 repeats. Despite the lack of molecular characterization of VprBP, recent studies suggest that VprBP can specifically associate with DDB1 to act as a substrate recognition subunit of the CUL4-DDB1 ubiquitin E3 ligase complex (12,20,26,33,36,38). Through binding to Vpr, VprBP allows Vpr to modulate the intrinsic catalytic activity of the CUL4-DDB1 complex, which in turn leads to the induction of G 2 phase cell cycle arrest in the virus-infected cells.…”

CRL4A-FBXW5–mediated degradation of DLC1 Rho GTPase-activating protein tumor suppressor promotes non-small cell lung cancer cell growth

“…Only two substrates have been reported to be related to cancer, as demonstrated by the degradation of Merlin and TSC2 tumor suppressor by VprBP (38) and FBXW5 (37), respectively. Therefore, we here add another tumor suppressor, DLC1, which is regulated by CRL4 complexes, implicating that CRL4 has cancer-related roles in addition to DNA-related functions.…”

Dyrk2-associated EDD-DDB1-VprBP E3 Ligase Inhibits Telomerase by TERT Degradation

“…In this complex, DDB1 functions as a linker protein between Cul4-Roc1 and VprBP (47). DDB1 is relatively larger than the substrate receptors for other proteins in the cullin family, implying that it is versatile in protein-protein interactions (31).…”