Role of α-Catenin and its mechanosensing properties in regulating Hippo/YAP-dependent tissue growth

PLoS Genet. 2019 Nov 7;15(11):e1008454. doi: 10.1371/journal.pgen.1008454. eCollection 2019 Nov.

Abstract

α-catenin is a key protein of adherens junctions (AJs) with mechanosensory properties. It also acts as a tumor suppressor that limits tissue growth. Here we analyzed the function of Drosophila α-Catenin (α-Cat) in growth regulation of the wing epithelium. We found that different α-Cat levels led to a differential activation of Hippo/Yorkie or JNK signaling causing tissue overgrowth or degeneration, respectively. α-Cat can modulate Yorkie-dependent tissue growth through recruitment of Ajuba, a negative regulator of Hippo signaling to AJs but also through a mechanism independent of Ajuba recruitment to AJs. Both mechanosensory regions of α-Cat, the M region and the actin-binding domain (ABD), contribute to growth regulation. Whereas M is dispensable for α-Cat function in the wing, individual M domains (M1, M2, M3) have opposing effects on growth regulation. In particular, M1 limits Ajuba recruitment. Loss of M1 causes Ajuba hyper-recruitment to AJs, promoting tissue-tension independent overgrowth. Although M1 binds Vinculin, Vinculin is not responsible for this effect. Moreover, disruption of mechanosensing of the α-Cat ABD affects tissue growth, with enhanced actin interactions stabilizing junctions and leading to tissue overgrowth. Together, our findings indicate that α-Cat acts through multiple mechanisms to control tissue growth, including regulation of AJ stability, mechanosensitive Ajuba recruitment, and dynamic direct F-actin interactions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton / genetics
  • Actins / genetics
  • Adherens Junctions / genetics
  • Animals
  • Cell Death / genetics
  • Cytoskeleton / genetics
  • Drosophila Proteins / genetics*
  • Drosophila melanogaster / genetics*
  • Drosophila melanogaster / growth & development
  • Epithelium / growth & development
  • Epithelium / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics
  • LIM Domain Proteins / genetics*
  • MAP Kinase Signaling System / genetics
  • Mechanotransduction, Cellular / genetics
  • Nuclear Proteins / genetics
  • Protein Domains / genetics
  • Protein Serine-Threonine Kinases / genetics
  • Trans-Activators / genetics
  • Vinculin / genetics
  • Wings, Animal / growth & development*
  • Wings, Animal / metabolism
  • YAP-Signaling Proteins
  • alpha Catenin / genetics*

Substances

  • Actins
  • Drosophila Proteins
  • Intracellular Signaling Peptides and Proteins
  • LIM Domain Proteins
  • Nuclear Proteins
  • Trans-Activators
  • YAP-Signaling Proteins
  • Yki protein, Drosophila
  • alpha Catenin
  • jub protein, Drosophila
  • Vinculin
  • Protein Serine-Threonine Kinases
  • hpo protein, Drosophila

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