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MBC in Press, published online ahead of print May 14, 2008
Mol. Biol. Cell 10.1091/mbc.E07-12-1219

A more recent version of this article appeared on August 1, 2008
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Submitted on December 6, 2007
Revised on March 28, 2008
Accepted on May 6, 2008

Ubiquitination of FGFR1 Is Required for Its Intracellular Sorting but Not for Its Endocytosis

Ellen Margrethe Haugsten,* Jêdrzej Malecki,*{dagger} Sunniva Maria Stordal Bjørklund,* Sjur Olsnes,* and Jørgen Wesche*

*Centre for Cancer Biomedicine, Faculty Division Norwegian Radium Hospital, University of Oslo, and Department of Biochemistry, Institute for Cancer Research, Norwegian Radium Hospital, Rikshospitalet University Hospital, Montebello, 0310 Oslo, Norway; {dagger}Jagiellonian University Medical College, 31-034 Krakow, Poland

Monitoring Editor: Jean E. Gruenberg

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 multi-lysine FGFR1 mutants, where up to 26 out of 29 lysines in the intracellular part of the receptor were mutated, retained tyrosine kinase activity. The active multi-lysine mutants were poorly ubiquitinated, but internalized normally, indicating that ubiquitination of the receptor is not required for endocytosis. In contrast, degradation of the multi-lysine 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 appears to be tightly regulated by receptor ubiquitination and subsequent sorting to the lysosomes for degradation.

Address correspondence to: Jørgen Wesche (Jorgen.Wesche{at}rr-research.no)




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