Ubiquitination and Degradation of the Hominoid-Specific Oncoprotein TBC1D3 Is Mediated by CUL7 E3 Ligase
Figure 8
The proposed model for CUL7-mediated TBC1D3 degradation.
TBC1D3 facilitates the propagation of GF-receptor signaling. In turn, GF stimulation induces TBC1D3 phosphorylation and phosphorylated TBC1D3 is recruited to Fbw8. CUL7 provides the structural backbone for the assembly of the CUL7-E3 ligase. The N-terminal portion of CUL7 binds to the adapter protein Skp1 that in turn binds the substrate recognition component, Fbw8. The RING E3 ligase associated with the C-terminus of CUL7 is called RBX1 or ROC1. It recruits an E2 ligase that provides the charged ubiquitin for transfer to the Fbw8-bound TBC1D3. TBC1D3 binds to CUL7 directly through the CPH domain as well as to Fbw8. TBC1D3 is degraded by CUL7-E3 ligase. This creates an inactivation loop that suppresses the effect of TBC1D3 on GF-receptor signaling. TBC1D3 binding to the CPH domain may also allow TBC1D3 to recruit CUL7 to unknown regulatory complexes where additional CUL7 substrates could be more efficiently ubiquitinated.
