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Membrane contacts between endosomes and ER provide sites for PTP1B–epidermal growth factor receptor interaction

Nature Cell Biology volume 12, pages 267–272 (2010)Cite this article

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Abstract

The epidermal growth factor receptor (EGFR) is a critical determinator of cell fate. Signalling from this receptor tyrosine kinase is spatially regulated by progression through the endocytic pathway, governing receptor half-life and accessibility to signalling proteins and phosphatases. Endocytosis of EGFR is required for interaction with the protein tyrosine phosphatase PTP1B (ref. 1), which localizes to the cytoplasmic face of the endoplasmic reticulum (ER)2, raising the question of how PTP1B comes into contact with endosomal EGFR. We show that EGFR–PTP1B interaction occurs by means of direct membrane contacts between the perimeter membrane of multivesicular bodies (MVBs) and the ER. The population of EGFR interacting with PTP1B is the same population that undergo ESCRT-mediated (endosomal sorting complex required for transport) sorting within MVBs, and PTP1B activity promotes the sequestration of EGFR on to MVB internal vesicles. Membrane contacts between endosomes and the ER form in both the presence and absence of stimulation by EGF. Thus membrane contacts between endosomes and the ER may represent a global mechanism for direct interaction between proteins on these two organelles.

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Figure 1: Expression of D181A-PTP1B inhibits lysosomal delivery and degradation of EGF.
Figure 2: Expressed D181A-PTP1B promotes and stabilizes MVB contact with the ER.
Figure 3: Membrane contact site formation is regulated by PTP1B.
Figure 4: Expression of wild-type (WT) PTP1B results in rapid EGFR and Hrs dephosphorylation and EGFR degradation.
Figure 5: PTP1B promotes inward vesiculation in EGFR-containing MVBs.

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Acknowledgements

We thank Lorna Bailey, Tim Levine, Steve Moss, Minoo Razi and the Futter laboratory and Institute of Ophthalmology EM unit members for technical help and advice. This work was funded by the Wellcome Trust (078304) and Cancer Research UK (C20675).

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  1. Ian J. White

    Present address: Present address: MRC Cell Biology Unit, Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT.,

  2. Emily R. Eden and Ian J. White: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Ophthalmology, University College London, 11–43 Bath Street, EC1V 9EL, London, UK

    Emily R. Eden, Ian J. White, Anna Tsapara & Clare E. Futter

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  1. Emily R. Eden
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E.R.E., I.J.W. and C.E.F. planned the work and drafted the manuscript. E.R.E., I.J.W. and A.T. did the experimental work and analysed the data.

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Correspondence to Clare E. Futter.

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Eden, E., White, I., Tsapara, A. et al. Membrane contacts between endosomes and ER provide sites for PTP1B–epidermal growth factor receptor interaction. Nat Cell Biol 12, 267–272 (2010). https://doi.org/10.1038/ncb2026

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