PLEKHA4/kramer Attenuates Dishevelled Ubiquitination to Modulate Wnt and Planar Cell Polarity Signaling

Cell Rep. 2019 May 14;27(7):2157-2170.e8. doi: 10.1016/j.celrep.2019.04.060.

Abstract

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.

Keywords: Cullin-3; Dishevelled; Drosophila; PI(4,5)P(2); Wnt signaling; kramer; phosphoinositide signaling; planar cell polarity; pleckstrin homology domain; ubiquitination.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Polarity*
  • Dishevelled Proteins / genetics
  • Dishevelled Proteins / metabolism*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster
  • HeLa Cells
  • Humans
  • Ubiquitination*
  • Wnt Signaling Pathway*

Substances

  • Dishevelled Proteins
  • Drosophila Proteins