TY - JOUR
T1 - An Unbiased Screen Identifies DEP-1 Tumor Suppressor as a Phosphatase Controlling EGFR Endocytosis
AU - Tarcic, Gabi
AU - Boguslavsky, Shlomit K.
AU - Wakim, Jean
AU - Kiuchi, Tai
AU - Liu, Angela
AU - Reinitz, Felicia
AU - Nathanson, David
AU - Takahashi, Takamune
AU - Mischel, Paul S.
AU - Ng, Tony
AU - Yarden, Yosef
N1 - Funding Information:
We thank G. Gur and A. Elson for insightful comments and A. Östman for reagents. Y.Y. is the incumbent of the Harold and Zelda Goldenberg Professorial Chair. This work was supported by research grants from the US National Cancer Institute (CA072981), the Israel Science Foundation, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and the German-Israeli Foundation. T.K. is supported by King's College London Breakthrough Research Unit funding.
PY - 2009/11/17
Y1 - 2009/11/17
N2 - 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.
AB - 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.
KW - SIGNALING
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U2 - 10.1016/j.cub.2009.09.048
DO - 10.1016/j.cub.2009.09.048
M3 - Article
C2 - 19836242
AN - SCOPUS:71849092111
VL - 19
SP - 1788
EP - 1798
JO - Current Biology
JF - Current Biology
SN - 0960-9822
IS - 21
ER -