FIGURE 10:

Model for CREB‑H phosphorylation at the S87/90 phosphodegron. The model illustrates the serine-rich area centering around the highly conserved residues S87–S90 in the N-terminus of CREB-HΔTMC, which we show is degraded in a proteasome-dependent manner and stabilized by substitution of S87A/S90A or inhibition of GSK-3 kinase or by interference with SCF activity by a dominant-negative strategy. Residues S87/90 are illustrated to be a key site for interaction with Fbw1a and thus for degradation by the SCF^Fbw1a complex in a manner dependent on phosphorylation by CKII but with augmented phosphorylation by GSK-3 at other sites, including the adjacent serine residues around S73–S81. Because GSK inhibition has a much more profound effect on CREB-H stabilization than mutation of the S73–S81 region, we propose that other sites within this region in downstream serines (e.g., 95–100) or indeed elsewhere in the protein may be involved, either as independent sites dictating interaction with SCF or in promoting the recognition of the key S87/90 site. As with other regulatory system, other kinases (x) are likely also to play a role, conferring flexibility upon CREB-H regulation and the ability to respond and integrate multiple metabolic or other stimuli.