Keratinocyte growth factor receptor ligands target the receptor to different intracellular pathways.
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.
Belleudi
Francesca
F
Dipartimento di Medicina Sperimentale, Università di Roma "La Sapienza", Viale Regina Elena 324, 00161 Roma, Italy.
Leone
Laura
L
Dipartimento di Medicina Sperimentale, Università di Roma "La Sapienza", Viale Regina Elena 324, 00161 Roma, Italy.
Nobili
Valerio
V
Dipartimento di Medicina Sperimentale, Università di Roma "La Sapienza", Viale Regina Elena 324, 00161 Roma, Italy.
Raffa
Salvatore
S
Dipartimento di Medicina Sperimentale, Università di Roma "La Sapienza", Viale Regina Elena 324, 00161 Roma, Italy.|Azienda Ospedaliera S. Andrea, via di Grottarossa, 1035-1039, 00189, Roma, Italy.
Francescangeli
Federica
F
Dipartimento di Medicina Sperimentale, Università di Roma "La Sapienza", Viale Regina Elena 324, 00161 Roma, Italy.
Maggio
Maddalena
M
Dipartimento di Medicina Sperimentale, Università di Roma "La Sapienza", Viale Regina Elena 324, 00161 Roma, Italy.
Morrone
Stefania
S
Dipartimento di Medicina Sperimentale, Università di Roma "La Sapienza", Viale Regina Elena 324, 00161 Roma, Italy.
Marchese
Cinzia
C
Dipartimento di Medicina Sperimentale, Università di Roma "La Sapienza", Viale Regina Elena 324, 00161 Roma, Italy.
Torrisi
Maria Rosaria
MR
Dipartimento di Medicina Sperimentale, Università di Roma "La Sapienza", Viale Regina Elena 324, 00161 Roma, Italy.|Azienda Ospedaliera S. Andrea, via di Grottarossa, 1035-1039, 00189, Roma, Italy.
D000818:Animals; D045744:Cell Line, Tumor; D004705:Endocytosis; D051526:Fibroblast Growth Factor 10 / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D011485:Protein Binding; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism*; D015398:Signal Transduction
C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; D051497:Receptor, Fibroblast Growth Factor, Type 2; C065104:keratinocyte growth factor receptor