AmotL2 disrupts apical-basal cell polarity and promotes tumour invasion

Nat Commun. 2014 Aug 1;5:4557. doi: 10.1038/ncomms5557.

Abstract

The establishment and maintenance of apical-basal cell polarity is essential for the functionality of glandular epithelia. Cell polarity is often lost in advanced tumours correlating with acquisition of invasive and malignant properties. Despite extensive knowledge regarding the formation and maintenance of polarity, the mechanisms that deregulate polarity in metastasizing cells remain to be fully characterized. Here we show that AmotL2 expression correlates with loss of tissue architecture in tumours from human breast and colon cancer patients. We further show that hypoxic stress results in activation of c-Fos-dependent expression of AmotL2 leading to loss of polarity. c-Fos/hypoxia-induced p60 AmotL2 interacts with the Crb3 and Par3 polarity complexes retaining them in large vesicles and preventing them from reaching the apical membrane. The resulting loss of polarity potentiates the response to invasive cues in vitro and in vivo in mice. These data provide a molecular mechanism how hypoxic stress deregulates cell polarity during tumour progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Breast Neoplasms / surgery
  • Caco-2 Cells
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Polarity
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • Colonic Neoplasms / surgery
  • Female
  • Gene Expression Regulation, Neoplastic*
  • HeLa Cells
  • Humans
  • Hypoxia / genetics*
  • Hypoxia / metabolism
  • Hypoxia / pathology
  • Lymph Nodes / metabolism
  • Lymph Nodes / pathology
  • Lymph Nodes / surgery
  • Mammary Glands, Human / metabolism
  • Mammary Glands, Human / pathology
  • Mammary Glands, Human / surgery
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, SCID
  • Neoplasm Invasiveness
  • Neoplasm Staging
  • Neoplasm Transplantation
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / metabolism
  • Signal Transduction
  • Transport Vesicles / metabolism

Substances

  • AMOTL2 protein, human
  • Adaptor Proteins, Signal Transducing
  • CRB3 protein, human
  • Carrier Proteins
  • Cell Cycle Proteins
  • Membrane Glycoproteins
  • Membrane Proteins
  • PARD3 protein, human
  • Proto-Oncogene Proteins c-fos