Recruitment of UBPY and ESCRT exchange drive HD-PTP-dependent sorting of EGFR to the MVB

Curr Biol. 2013 Mar 18;23(6):453-61. doi: 10.1016/j.cub.2013.02.033. Epub 2013 Mar 7.


Background: Sorting ubiquitinated epidermal growth factor receptor (EGFR) to the intralumenal vesicles of the multivesicular body requires the coordinated action of several ESCRT complexes. A central question is how EGFR transits vectorially from early, ubiquitin-binding ESCRTs to the final complex, ESCRT-III, such that cargo sequestration is coupled with intralumenal vesicle formation.

Results: We show that the ESCRT accessory protein HD-PTP/PTPN23 associates with EGFR and combines with the deubiquitinating enzyme UBPY/USP8 to transfer EGFR from ESCRT-0 to ESCRT-III and drive EGFR sorting to intralumenal vesicles. HD-PTP binds ESCRT-0 via two interactions with the STAM2 subunit. First, the HD-PTP Bro1 domain binds the core domain of STAM2. This is competed by the ESCRT-III subunit CHMP4B, which binds an overlapping site on HD-PTP Bro1. Second, a proline-rich peptide in HD-PTP binds the SH3 domain of STAM2. Similar proline-rich peptides on UBPY also bind STAM2 SH3 to facilitate EGFR deubiquitination. Hence, locally recruited UBPY would be expected to compete with HD-PTP for STAM2 binding at this second site. Indeed, we show that HD-PTP recruits UBPY to EGFR. Association of UBPY with HD-PTP involves UBPY interacting with HD-PTP-bound CHMP4B, as well as additional interaction(s) between UBPY and HD-PTP.

Conclusions: This study identifies HD-PTP as a central coordinator of the ESCRT pathway for EGFR. Based on these studies, we propose a model whereby the concerted recruitment of CHMP4B and UBPY to HD-PTP and the engagement of UBPY by STAM2 displaces ESCRT-0 from HD-PTP, deubiquitinates EGFR, and releases ESCRT-0 from cargo in favor of ESCRT-III.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Electron Microscope Tomography
  • Endopeptidases / metabolism*
  • Endosomal Sorting Complexes Required for Transport / metabolism*
  • ErbB Receptors / metabolism*
  • Fluorescent Antibody Technique
  • HeLa Cells
  • Humans
  • Mice
  • Multivesicular Bodies / metabolism*
  • Protein Transport*
  • Protein Tyrosine Phosphatases, Non-Receptor / metabolism*
  • Saccharomyces cerevisiae
  • Two-Hybrid System Techniques
  • Ubiquitin Thiolesterase / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Endosomal Sorting Complexes Required for Transport
  • STAM2 protein, human
  • EGFR protein, human
  • ErbB Receptors
  • PTPN23 protein, human
  • Protein Tyrosine Phosphatases, Non-Receptor
  • Endopeptidases
  • USP8 protein, human
  • Ubiquitin Thiolesterase