An Unbiased Screen Identifies DEP-1 Tumor Suppressor as a Phosphatase Controlling EGFR Endocytosis

Gabi Tarcic, Shlomit K. Boguslavsky, Jean Wakim, Tai Kiuchi, Angela Liu, Felicia Reinitz, David Nathanson, Takamune Takahashi, Paul S. Mischel, Tony Ng, Yosef Yarden

    Research output: Contribution to journalArticlepeer-review

    81 Citations (Scopus)

    Abstract

    Background: The epidermal growth factor (EGF) stimulates rapid tyrosine phosphorylation of the EGF receptor (EGFR). This event precedes signaling from both the plasma membrane and from endosomes, and it is essential for recruitment of a ubiquitin ligase, CBL, that sorts activated receptors to endosomes and degradation. Because hyperphosphorylation of EGFR is involved in oncogenic pathways, we performed an unbiased screen of small interfering RNA (siRNA) oligonucleotides targeting all human tyrosine phosphatases. Results: We report the identification of PTPRK and PTPRJ (density-enhanced phosphatase-1 [DEP-1]) as EGFR-targeting phosphatases. DEP-1 is a tumor suppressor that dephosphorylates and thereby stabilizes EGFR by hampering its ability to associate with the CBL-GRB2 ubiquitin ligase complex. DEP-1 silencing enhanced tyrosine phosphorylation of endosomal EGFRs and, accordingly, increased cell proliferation. In line with functional interactions, EGFR and DEP-1 form physical associations, and EGFR phosphorylates a substrate-trapping mutant of DEP-1. Interestingly, the interactions of DEP-1 and EGFR are followed by physical segregation: whereas EGFR undergoes endocytosis, DEP-1 remains confined to the cell surface. Conclusions: EGFR and DEP-1 physically interact at the cell surface and maintain bidirectional enzyme-substrate interactions, which are relevant to their respective oncogenic and tumor-suppressive functions. These observations highlight the emerging roles of vesicular trafficking in malignant processes.

    Original languageEnglish
    Pages (from-to)1788-1798
    Number of pages11
    JournalCurrent Biology
    Volume19
    Issue number21
    DOIs
    Publication statusPublished - 2009 Nov 17

    Keywords

    • SIGNALING

    ASJC Scopus subject areas

    • Biochemistry, Genetics and Molecular Biology(all)
    • Agricultural and Biological Sciences(all)

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