Endocytosis of GM-CSF receptor β is essential for signal transduction regulating mesothelial-macrophage transition

Viktória Zsiros, Sándor Katz, Nikolett Doczi, A. Kiss

Research output: Contribution to journalArticle

Abstract

During Freund's adjuvant induced inflammation rat mesenteric mesothelial cells transdifferentiate into mesenchymal cell. They express macrophage markers, inflammatory cytokines (TGF-β, TNFα, IL-6), and specific receptors. When primary mesenteric cultures were treated with GM-CSF and/or TGF-β (in vitro), similar phenotypic and biological changes were induced. It seemed likely that GM-CSF receptor-ligand complex should be internalized to initiate mesothelial-macrophage transition. To follow the intracellular route of GM-CSF receptor β, we co-localized this receptor with various endocytic markers (Cav-1, EEA1, Rab7, and Rab11a), and carried out detailed immunocytochemical, statistical and biochemical analyses. Since STAT5 is one of the downstream element of GM-CSF signaling, we followed the expression and phosphorylation level of this transcription factor. Our results showed that in mesenteric mesothelial cells GM-CSF receptor β is internalized by caveolae, delivered into early endosomes where the signaling events occur, STAT5A is phosphorylated by JAK2, and then translocated into the nucleus. When dynamin-dependent endocytosis of GM-CSFR β is inhibited by dynasore, phosphorylation of STAT5A is not occurred, confirming, that the internalization of receptor β is indispensable for signal transduction. At the early time of inflammation a significant receptor recycling can be found to the plasma membrane. Later (day 8) the receptor is delivered into late endosomes, indicating that its degradation has already started, and the regeneration of mesothelial cells can start. All of these data strongly support that the internalization of GM-CSF receptor β is required and essential for signal transduction.

Original languageEnglish
Pages (from-to)1450-1462
Number of pages13
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1866
Issue number9
DOIs
Publication statusPublished - Sep 1 2019

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Granulocyte-Macrophage Colony-Stimulating Factor Receptors
Endocytosis
Signal Transduction
Macrophages
Endosomes
Granulocyte-Macrophage Colony-Stimulating Factor
Phosphorylation
Inflammation
Dynamins
Interleukin-6 Receptors
Caveolae
Freund's Adjuvant
Regeneration
Transcription Factors
Cell Membrane
Cytokines
Ligands

Keywords

  • Epithelial-mesenchymal transition
  • Granulocyte-macrophage colony-stimulating factor
  • Inflammation
  • Internalization
  • Mesothelial cell
  • Signaling

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Endocytosis of GM-CSF receptor β is essential for signal transduction regulating mesothelial-macrophage transition. / Zsiros, Viktória; Katz, Sándor; Doczi, Nikolett; Kiss, A.

In: Biochimica et Biophysica Acta - Molecular Cell Research, Vol. 1866, No. 9, 01.09.2019, p. 1450-1462.

Research output: Contribution to journalArticle

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