Involvement of JAK2 upstream of the PI 3-kinase in cell-cell adhesion regulation by gastrin

Exp Cell Res. 2004 Dec 10;301(2):128-38. doi: 10.1016/j.yexcr.2004.07.037.

Abstract

The Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway has been implicated in cell transformation and proliferation. Besides aberrant cell proliferation, loss of cell-cell adhesion during epithelial-mesenchymal transition (EMT) is an important event which occurs during development of epithelial cancers. However, the role of JAK-dependent pathways in this process is not known. We analyzed the involvement of these pathways in the regulation of E-cadherin-dependent cell-cell adhesion by gastrin, a mitogenic factor for gastrointestinal (GI) tract. We identified JAK2/STAT3 as a new pathway in gastrin signaling. We demonstrated that JAK2 functions as an upstream mediator of the phosphatidylinositol 3 (PI 3)-kinase activity in gastrin signaling. Indeed, we observed a coprecipitation of both kinases and an inhibition of gastrin-induced PI 3-kinase activation when JAK2 activity is blocked. We also demonstrated that loss of cell-cell adhesion and the increase in cell motility induced by gastrin required the activation of JAK2 and the PI 3-kinase. Indeed, the modifications in localization of adherens junctions proteins and the migration, observed in gastrin-stimulated cells, were reversed by inhibition of both kinases. These results described the involvement of JAK2 in the modulation of cell-cell adhesion in epithelial cells. They support a possible role of JAK2 in the epithelial-mesenchymal transition which occurs during malignant development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / drug effects
  • Adherens Junctions / drug effects
  • Animals
  • Cell Adhesion*
  • Cell Line
  • Cell Movement / drug effects
  • DNA-Binding Proteins / metabolism
  • Enzyme Activation
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Gastrins / physiology*
  • Janus Kinase 2
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation
  • Protein-Tyrosine Kinases / physiology*
  • Proto-Oncogene Proteins / physiology*
  • Rats
  • STAT3 Transcription Factor
  • Time Factors
  • Trans-Activators / metabolism
  • Wound Healing

Substances

  • DNA-Binding Proteins
  • Gastrins
  • Proto-Oncogene Proteins
  • STAT3 Transcription Factor
  • Stat3 protein, rat
  • Trans-Activators
  • Phosphatidylinositol 3-Kinases
  • Protein-Tyrosine Kinases
  • Jak2 protein, rat
  • Janus Kinase 2