The mechanisms by which malignant tumors leave the primary tumor site, invade lymphatics, and metastasize to regional lymph nodes (RLNs) are complex and interrelated. Although the phenomenon of lymph node metastasis has been rec-

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Background The epidermal growth factor (EGF) stimulates rapid tyrosine phosphorylation of EGF-receptor (EGFR). This event precedes signalling from both the plasma membrane and from endosomes, and it is essential for recruitment of an ubiquitin ligase, CBL, that sorts activated receptors to endosomes and degradation. Because hyper-phosphorylation of EGFR is involved in oncogenic pathways, we performed an unbiased screen of siRNA oilgonucleotides targeting all human tyrosine phosphatases. Results We report the identification of PTPRK and PTPRJ (DEP-1) as EGFR-targeting phosphatases. DEP-1 is a tumour suppressor that dephosphorylates, 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 substrtae 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 maitain 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.

Among women with similar medical care access since before their diagnoses, we found ethnic differences in stage of breast cancer at diagnosis. Adjustment for this difference and for income, age, and marital status resulted in a negligible effect of race on survival.