YWK-II/APLP2 inhibits TGF-β signaling by interfering with the TGFBR2-Hsp90 interaction

Transforming growth factor-β (TGF-β) regulates multiple cellular biological processes by activating TGF-β type I receptors (TGFBR1) and type II receptors (TGFBR2), and Hsp90 stabilizes these receptors through specific interactions. In many malignancies, one of the most deregulated signaling pathways is the TGF-β signaling pathway, which is often inactivated by mutations or deregulation of TGF-β type II receptors (TGFBR2). However, the molecular mechanisms are not well understood. In this study, we show that YWK-II/APLP2, an immediately early response gene for TGF-β signaling, inhibits TGF-β signaling by promoting the degradation of the TGFBR2 protein. Knockdown of YWK-II/APLP2 increases the TGFBR2 protein level and sensitizes cells to TGF-β stimulation, while YWK-II/APLP2 overexpression destabilizes TGFBR2 and desensitizes cells to TGF-β. Mechanistically, YWK-II/APLP2 is associated with TGFBR2 in a TGF-β activity-dependent manner, binds to Hsp90 to interfere with the interaction between TGFBR2 and Hsp90, and leads to enhanced ubiquitination and degradation of TGFBR2. Taken together, YWK-II/APLP2 is involved in negatively regulating the duration and intensity of TGF-β/Smad signaling and suggests that aberrantly high expression of YWK-II/APLP2 in malignancies may antagonize the growth inhibition mediated by TGF-β signaling and play a role in carcinogenesis.