Factors secreted by tumor cells shape the local microenvironment to promote invasion and metastasis, as well as condition the pre-metastatic niche to enable secondary-site colonization and growth. In addition to this secretome, tumor cells have increased abundance of growth-promoting receptors at the cell surface. We found that the tyrosine phosphatase PTPN14 (also called Pez, which is mutated in various cancers) suppressed metastasis of breast cancer xenografts, in part by reducing intracellular protein trafficking through the secretory pathway (Belle et al, 2015). PTPN14 activity also decreased the abundance of EGFR (epidermal growth factor receptor) at the surface of breast cancer cells. We identified RIN1 (Ras and Rab interactor 1) and PRKCD (protein kinase C Î´), amongst others, as binding partners and substrates of PTPN14 by quantitative phosphoproteomics and found that they promoted secretion of soluble factors and cell-surface EGFR. Invasive breast cancer tissue had decreased expression of PTPN14, and patient survival was worse when tumors had increased expression of the gene encoding PRKCD. Thus, PTPN14 prevents metastasis by restricting the trafficking of both soluble and membrane-bound proteins to the cell surface. Our initial analysis of cancer-associated mutations of PTPN14 indicates that some PTPN14 mutations are indeed loss-of-function mutations, supporting its role as a tumour/metastasis suppressor. In unpublished studies, we have also analysed the effects of PTPN14 and its substrates on anchorage independent growth and survival and identified a potential role of PTPN14 and its substrate PRKCD in recruitment of Rabs to the endosomal compartments to control protein trafficking. We have made novel observations in alterations in Rab recruitment in cells lacking PTPN14 which are also observed in breast cancer patient specimens. We are currently also building a network of phosphatases and kinases that regulate protein trafficking to develop novel strategies for reducing growth factor signalling in cancer cells. Ref: Belle L et al (2015) Sci Signaling 33:ra18.