Ubiquitination of fibroblast growth factor receptor 1 is required for its intracellular sorting but not for its endocytosis.
Endocytosis and targeting of growth factor receptors for lysosomal degradation have been associated with ubiquitination of the intracellular part of the receptors. To elucidate the role of receptor ubiquitination in internalization and sorting of fibroblast growth factor receptor (FGFR), we constructed several mutants of FGFR1 in which lysines, potential ubiquitination sites, were substituted for arginines. Substitution of all lysine residues in the intracellular part of FGFR1 resulted in inactivation of the tyrosine kinase domain of the receptor. However, several multilysine FGFR1 mutants, where up to 26 of 29 lysines in the intracellular part of the receptor were mutated, retained tyrosine kinase activity. The active multilysine mutants were poorly ubiquitinated, but internalized normally, indicating that ubiquitination of the receptor is not required for endocytosis. In contrast, degradation of the multilysine mutants was dramatically reduced as the mutants were inefficiently transported to lysosomes but rather sorted to recycling endosomes. The altered sorting resulted in sustained signaling. The duration of FGFR1 signaling seems to be tightly regulated by receptor ubiquitination and subsequent sorting to the lysosomes for degradation.
Haugsten
Ellen Margrethe
EM
Centre for Cancer Biomedicine, Faculty Division Norwegian Radium Hospital, University of Oslo, 0310 Oslo, Norway.
Malecki
Jedrzej
J
Bjørklund
Sunniva Maria Stordal
SM
Olsnes
Sjur
S
Wesche
Jørgen
J
D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000235:genetics; D015536:Down-Regulation; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008239:Lysine / Q000737:chemistry; D008247:Lysosomes / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D021381:Protein Transport; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D025801:Ubiquitin / Q000737:chemistry
D017468:Receptors, Fibroblast Growth Factor; D025801:Ubiquitin; D051496:Receptor, Fibroblast Growth Factor, Type 1; D008239:Lysine