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Published online
doi:10.1083/jcb.200708115
The Journal of Cell Biology, Vol. 180, No. 6, 1205-1218
The Rockefeller University Press, 0021-9525 $30.00
© Roxrud et al.
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Article

An endosomally localized isoform of Eps15 interacts with Hrs to mediate degradation of epidermal growth factor receptor



Ingrid Roxrud1,2, Camilla Raiborg1,2, Nina Marie Pedersen1,2, Espen Stang3, and Harald Stenmark1,2

1 Centre for Cancer Biomedicine and 2 Department of Biochemistry, University of Oslo and the Norwegian Radium Hospital, Montebello, N-0310 Oslo, Norway
3 Institute of Pathology, Rikshospitalet, University of Oslo, N-0027 Oslo, Norway

Correspondence to H. Stenmark: stenmark{at}ulrik.uio.no

Down-regulation of activated and ubiquitinated growth factor (GF) receptors by endocytosis and subsequent lysosomal degradation ensures attenuation of GF signaling. The ubiquitin-binding adaptor protein Eps15 (epidermal growth factor receptor [EGFR] pathway substrate 15) functions in endocytosis of such receptors. Here, we identify an Eps15 isoform, Eps15b, and demonstrate its expression in human cells and conservation across vertebrate species. Although both Eps15 and Eps15b interact with the endosomal sorting protein Hrs (hepatocyte growth factor–regulated tyrosine kinase substrate) in vitro, we find that Hrs specifically binds Eps15b in vivo (whereas adaptor protein 2 preferentially interacts with Eps15). Although Eps15 mainly localizes to clathrin-coated pits at the plasma membrane, Eps15b localizes to Hrs-positive microdomains on endosomes. Eps15b overexpression, similarly to Hrs overexpression, inhibits ligand-mediated degradation of EGFR, whereas Eps15 is without effect. Similarly, depletion of Eps15b but not Eps15 delays degradation and promotes recycling of EGFR. These results indicate that Eps15b is an endosomally localized isoform of Eps15 that is present in the Hrs complex via direct Hrs interaction and important for the sorting function of this complex.

Abbreviations used in this paper: AP2, adaptor protein 2; EEA1, early endosomal antigen 1; EGFR, EGF receptor; EH, Eps15 homology; Eps15, EGFR pathway substrate 15; ESCRT, endosomal sorting complex required for transport; Hrs, hepatocyte growth factor–regulated tyrosine kinase substrate; STAM, signal-transducing adaptor molecule; TSS, transcriptional start site, UIM, ubiquitin-interacting motif.


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