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Disruption of the Cdc42/Par6/aPKC or Dlg/Scrib/Lgl Polarity Complex Promotes Epithelial Proliferation via Overlapping

Gregory V Schimizzi1,2,3, Meghan T Maher1,2,3, Andrew J Loza1,3,4

  • 1ICCE Institute, Washington University School of Medicine, St. Louis, Missouri, United States of America.

Plos One
|July 26, 2016
PubMed

Insights

Disrupting epithelial polarity proteins, crucial for tissue structure and tumor suppression, triggers distinct cell proliferation pathways. This study reveals how basal complex disruption leads to JNK-driven growth, while junctional complex disruption activates p38 signaling.

Area of Science:

  • Cell Biology
  • Developmental Biology
  • Cancer Biology

Background:

  • Apical-basal polarity (ABP) is fundamental for epithelial function and acts as a tumor suppressor mechanism.
  • Disruption of ABP proteins is an early event in cancer, leading to uncontrolled proliferation and tissue disorganization.
  • The precise signaling pathways mediating proliferation upon ABP disruption remain incompletely understood.

Purpose of the Study:

  • To investigate the distinct downstream signaling pathways activated by the disruption of basal versus junctional polarity complexes.
  • To elucidate the roles of specific signaling cascades, including JNK, p38, and Rho-Rok-Myosin, in epithelial proliferation following polarity loss.
  • To examine the influence of Tumor Necrosis Factor (TNF) signaling on proliferation induced by ABP disruption.

Main Methods:

  • Utilized the proliferating Drosophila melanogaster wing disc epithelium as a model system.
  • Genetically disrupted basal and junctional polarity complexes to observe effects on epithelial proliferation.
  • Analyzed downstream signaling pathways, including JNK, p38, and Rho-Rok-Myosin contractility.
  • Investigated the role of non-autonomous TNF signaling and the actin regulator Moesin.

Main Results:

  • Disruption of the basal polarity complex induced JNK-dependent epithelial proliferation.
  • Disruption of the junctional complex primarily led to p38-dependent proliferation.
  • The Rho-Rok-Myosin contractility apparatus exhibited opposing roles depending on which polarity complex was disrupted.
  • Non-autonomous TNF signaling suppressed proliferation caused by either basal or junctional complex disruption.
  • JNK activation by junctional complex disruption occurred via Rho-Rok-Myosin, independently of Moesin.

Conclusions:

  • Epithelial polarity complexes regulate proliferation through distinct signaling pathways (JNK vs. p38).
  • The Rho-Rok-Myosin pathway's role in proliferation is context-dependent on the specific polarity complex affected.
  • TNF signaling acts as a general suppressor of proliferation triggered by apical-basal polarity loss.
  • Understanding these pathways provides insights into early cancer development and potential therapeutic targets.

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