Keratinocyte growth factor receptor ligands target the receptor to different intracellular pathways

Francesca Belleudi, Laura Leone, Valerio Nobili, Salvatore Raffa, Federica Francescangeli, Maddalena Maggio, Stefania Morrone, Cinzia Marchese, Maria Rosaria Torrisi

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

The keratinocyte growth factor receptor (KGFR)/fibroblast growth factor receptor 2b is activated by high-affinity-specific interaction with two different ligands, keratinocyte growth factor (KGF)/fibroblast growth factor (FGF)7 and FGF10/KGF2, which are characterized by an opposite requirement of heparan sulfate proteoglycans and heparin for binding to the receptor. We investigated here the possible different endocytic trafficking of KGFR, induced by the two ligands. Immunofluorescence and immunoelectron microscopy analysis showed that KGFR internalization triggered by either KGF or FGF10 occurs through clathrin-coated pits. Immunofluorescence confocal microscopy using endocytic markers as well as tumor susceptibility gene 101 (TSG101) silencing demonstrated that KGF drives KGFR to the degradative pathway, while FGF10 targets the receptor to the recycling endosomes. Biochemical analysis showed that KGFR is ubiquitinated and degraded after KGF treatment but not after FGF10 treatment, and that the alternative fate of KGFR might depend on the different ability of the receptor to phosphorylate the fibroblast growth factor receptor substrate 2 (FRS2) substrate and to recruit the ubiquitin ligase c-Cbl. The recycling endocytic pathway followed by KGFR upon FGF10 stimulation correlates with the higher mitogenic activity exerted by this ligand on epithelial cells compared with KGF, suggesting that the two ligands may play different functional roles through the regulation of the receptor endocytic transport.

Original languageEnglish
Pages (from-to)1854-1872
Number of pages19
JournalTraffic
Volume8
Issue number12
DOIs
Publication statusPublished - Dec 2007

Fingerprint

Fibroblast Growth Factor 7
Ligands
Receptor, Fibroblast Growth Factor, Type 2
Fluorescence Microscopy
Recycling
Fibroblast Growth Factor Receptors
Heparan Sulfate Proteoglycans
Clathrin
Immunoelectron Microscopy
Confocal microscopy
Endosomes
Gene Silencing
Substrates
Ligases
Ubiquitin
keratinocyte growth factor receptor
Confocal Microscopy
Heparin
Microscopic examination
Epithelial Cells

Keywords

  • Endocytosis
  • Fibroblast growth factor 10
  • Keratinocyte growth factor
  • Keratinocyte growth factor receptor
  • Receptor tyrosine kinases

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Structural Biology
  • Molecular Biology
  • Genetics

Cite this

Keratinocyte growth factor receptor ligands target the receptor to different intracellular pathways. / Belleudi, Francesca; Leone, Laura; Nobili, Valerio; Raffa, Salvatore; Francescangeli, Federica; Maggio, Maddalena; Morrone, Stefania; Marchese, Cinzia; Torrisi, Maria Rosaria.

In: Traffic, Vol. 8, No. 12, 12.2007, p. 1854-1872.

Research output: Contribution to journalArticle

Belleudi, F, Leone, L, Nobili, V, Raffa, S, Francescangeli, F, Maggio, M, Morrone, S, Marchese, C & Torrisi, MR 2007, 'Keratinocyte growth factor receptor ligands target the receptor to different intracellular pathways', Traffic, vol. 8, no. 12, pp. 1854-1872. https://doi.org/10.1111/j.1600-0854.2007.00651.x
Belleudi, Francesca ; Leone, Laura ; Nobili, Valerio ; Raffa, Salvatore ; Francescangeli, Federica ; Maggio, Maddalena ; Morrone, Stefania ; Marchese, Cinzia ; Torrisi, Maria Rosaria. / Keratinocyte growth factor receptor ligands target the receptor to different intracellular pathways. In: Traffic. 2007 ; Vol. 8, No. 12. pp. 1854-1872.
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