PLEKHA4/kramer Attenuates Dishevelled Ubiquitination to Modulate Wnt and Planar Cell Polarity Signaling
Adnan Shami Shah,
Alex G. Batrouni,
Dongsung Kim,
Amith Punyala,
Wendy Cao,
Chun Han,
Michael L. Goldberg,
Marcus B. Smolka,
Jeremy M. Baskin
Affiliations
Adnan Shami Shah
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA; Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA
Alex G. Batrouni
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA; Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA
Dongsung Kim
Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA; Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA
Amith Punyala
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA; Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA
Wendy Cao
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA; Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA
Chun Han
Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA; Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA
Michael L. Goldberg
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA
Marcus B. Smolka
Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA; Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA
Jeremy M. Baskin
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA; Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA; Corresponding author
Summary: Wnt signaling pathways direct key physiological decisions in development. Here, we establish a role for a pleckstrin homology domain-containing protein, PLEKHA4, as a modulator of signaling strength in Wnt-receiving cells. PLEKHA4 oligomerizes into clusters at PI(4,5)P2-rich regions of the plasma membrane and recruits the Cullin-3 (CUL3) E3 ubiquitin ligase substrate adaptor Kelch-like protein 12 (KLHL12) to these assemblies. This recruitment decreases CUL3-KLHL12-mediated polyubiquitination of Dishevelled, a central intermediate in canonical and non-canonical Wnt signaling. Knockdown of PLEKHA4 in mammalian cells demonstrates that PLEKHA4 positively regulates canonical and non-canonical Wnt signaling via these effects on the Dishevelled polyubiquitination machinery. In vivo knockout of the Drosophila melanogaster PLEKHA4 homolog, kramer, selectively affects the non-canonical, planar cell polarity (PCP) signaling pathway. We propose that PLEKHA4 tunes the sensitivities of cells toward the stimulation of Wnt or PCP signaling by sequestering a key E3 ligase adaptor controlling Dishevelled polyubiquitination within PI(4,5)P2-rich plasma membrane clusters. : Regulation of Wnt signaling is critical to metazoan development. Shami Shah et al. identify a phosphoinositide-binding protein, PLEKHA4/kramer, that enhances Wnt signaling in mammalian cells and the non-canonical pathway, planar cell polarity, in Drosophila. Mechanistically, PLEKHA4 sequesters the Cullin-3 E3 ligase adaptor KLHL12 in plasma membrane clusters, preventing Dishevelled polyubiquitination. Keywords: phosphoinositide signaling, PI(4,5)P2, pleckstrin homology domain, ubiquitination, Cullin-3, Dishevelled, Wnt signaling, planar cell polarity, Drosophila, kramer
