Abstract
The four-pass transmembrane proteins Vangl1 and Vangl2 are dedicated core components of Wnt/planar cell polarity (Wnt/PCP) signaling that critically regulate polarized cell behaviors in many morphological and physiological processes. Here, we found that the abundance of Vangl proteins is tightly controlled by the ubiquitin-proteasome system through endoplasmic reticulum-associated degradation (ERAD). The key ERAD component p97/VCP directly binds to Vangl at a highly conserved VCP-interacting motif and recruits the E3 ligase KBTBD7 via its UBA-UBX adaptors to promote Vangl ubiquitination and ERAD. We found that Wnt5a/CK1 prevents Vangl ubiquitination and ERAD by inducing Vangl phosphorylation, which facilitates Vangl export from the ER to the plasma membrane. We also provide in vivo evidence that KBTBD7 regulates convergent extension during zebrafish gastrulation and functions as a tumor suppressor in breast cancer by promoting Vangl degradation. Our findings reveal a previously unknown regulatory mechanism of Wnt/PCP signaling through the p97/VCP-KBTBD7-mediated ERAD pathway.
Highlights
Wnt signaling is an evolutionarily conserved cellular mechanism that regulates nearly every aspect of development and homeostasis in both physiological and pathological conditions [1]
We showed here that KBTBD7, a Cullin 3 (CUL3) substrate recognition protein, functions as a negative regulator of Wnt/planar cell polarity (Wnt/planar cell polarity (PCP)) signaling by regulating Vangl protein levels through ubiquitination
A key molecular feature of PCP is the asymmetric distribution of core proteins in planar polarized tissues, in which Fz/Dsh/Dgo and Van Gogh (Vang)/Pk protein complexes segregate to the opposite sides of the cell, and Fmi forms homodimers across neighboring cell membranes
Summary
Wnt signaling is an evolutionarily conserved cellular mechanism that regulates nearly every aspect of development and homeostasis in both physiological and pathological conditions [1]. Genetic studies in drosophila identified a group of core PCP proteins: Frizzled (Fz), Van Gogh (Vang), Dishevelled (Dsh), Prickle (Pk), Diego (Dgo), and Flamingo (Fmi), which control the orientation of bristles and hairs on the body and the arrangement of ommatidia in the compound eye [4]. In vertebrates such as zebrafish, PCP is required for a process known as convergent extension (CE) movement, which contributes to the elongation of their anterior- posterior (A-P) body axis [5]. This pathway is sensitive to the levels of the core PCP proteins, as the establishment of PCP asymmetry depends on both the intracellular and intercellular interactions of these proteins
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