The Spectrin cytoskeleton regulates the Hippo signalling pathway

EMBO J. 2015 Apr 1;34(7):940-54. doi: 10.15252/embj.201489642. Epub 2015 Feb 23.

Abstract

The Spectrin cytoskeleton is known to be polarised in epithelial cells, yet its role remains poorly understood. Here, we show that the Spectrin cytoskeleton controls Hippo signalling. In the developing Drosophila wing and eye, loss of apical Spectrins (alpha/beta-heavy dimers) produces tissue overgrowth and mis-regulation of Hippo target genes, similar to loss of Crumbs (Crb) or the FERM-domain protein Expanded (Ex). Apical beta-heavy Spectrin binds to Ex and co-localises with it at the apical membrane to antagonise Yki activity. Interestingly, in both the ovarian follicular epithelium and intestinal epithelium of Drosophila, apical Spectrins and Crb are dispensable for repression of Yki, while basolateral Spectrins (alpha/beta dimers) are essential. Finally, the Spectrin cytoskeleton is required to regulate the localisation of the Hippo pathway effector YAP in response to cell density human epithelial cells. Our findings identify both apical and basolateral Spectrins as regulators of Hippo signalling and suggest Spectrins as potential mechanosensors.

Keywords: Hippo signalling; Spectrin; YAP; cytoskeleton.

MeSH terms

  • Animals
  • Cell Line
  • Cytoskeleton / genetics
  • Cytoskeleton / metabolism*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster
  • Female
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mechanotransduction, Cellular / physiology*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Ovarian Follicle / cytology
  • Ovarian Follicle / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Spectrin / genetics
  • Spectrin / metabolism*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism

Substances

  • Drosophila Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Nuclear Proteins
  • Trans-Activators
  • Yki protein, Drosophila
  • crb protein, Drosophila
  • ex protein, Drosophila
  • Spectrin
  • Protein-Serine-Threonine Kinases
  • hpo protein, Drosophila