A role for Hrs in endosomal sorting of ligand-stimulated and unstimulated epidermal growth factor receptor.
Ligand-stimulated growth factor receptors are rapidly internalized and transported to early endosomes. Unstimulated receptors are also internalized constitutively, although at a slower rate, and delivered to the same organelle. At early endosomes, stimulated receptors are sorted for the lysosomal degradation pathway, whereas unstimulated receptors are mostly recycled back to the cell surface. To investigate the role of Hrs, an early endosomal protein, in this sorting process, we overexpressed Hrs in HeLa cells and examined the intracellular trafficking of epidermal growth factor receptor (EGFR) in EGF-stimulated and unstimulated cells. Overexpression of Hrs inhibited the trafficking of EGFR from early endosomes, resulting in an accumulation of EGFR on early endosomes in both ligand-stimulated and unstimulated cells. On the other hand, overexpression of Hrs mutants with a deletion or a point mutation within the FYVE domain did not inhibit the trafficking. These results suggest that Hrs regulates the sorting of ligand-stimulated and unstimulated growth factor receptors on early endosomes, and that the FYVE domain, which is required for Hrs to reside in a microdomain of early endosomes, plays an essential role in the function of Hrs.
Morino
Chitose
C
Department of Biological Sciences, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Midori, Yokohama 226-8501, Japan.
Kato
Masaki
M
Yamamoto
Akitsugu
A
Mizuno
Emi
E
Hayakawa
Akira
A
Komada
Masayuki
M
Kitamura
Naomi
N
D056827:Endosomal Sorting Complexes Required for Transport; D011992:Endosomes / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D019084:Fluorescent Antibody Technique, Indirect; D017353:Gene Deletion; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D021962:Membrane Microdomains / Q000737:chemistry; D016253:Microscopy, Immunoelectron; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D017354:Point Mutation; D011233:Precipitin Tests; D017434:Protein Structure, Tertiary / Q000235:genetics; D021381:Protein Transport
D056827:Endosomal Sorting Complexes Required for Transport; D008024:Ligands; D010750:Phosphoproteins; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate; D004815:Epidermal Growth Factor; D066246:ErbB Receptors