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Sci Signal. 2015 Feb 17;8(364):ra18. doi: 10.1126/scisignal.2005547.

The tyrosine phosphatase PTPN14 (Pez) inhibits metastasis by altering protein trafficking.

Author information

1
Centre for Cancer Biology, an Alliance between SA Pathology and University of South Australia, Adelaide, South Australia 5000, Australia. Discipline of Biochemistry, School of Molecular and Biomedical Science, The University of Adelaide, Adelaide, South Australia 5005, Australia.
2
Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.
3
Centre for Cancer Biology, an Alliance between SA Pathology and University of South Australia, Adelaide, South Australia 5000, Australia. Department of Medicine, The University of Adelaide, Adelaide, South Australia 5005, Australia.
4
Centre for Cancer Biology, an Alliance between SA Pathology and University of South Australia, Adelaide, South Australia 5000, Australia.
5
Cancer Research Program, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.
6
Division of Tissue Pathology, SA Pathology, Adelaide, South Australia 5000, Australia.
7
Centre for Cancer Biology, an Alliance between SA Pathology and University of South Australia, Adelaide, South Australia 5000, Australia. Department of Medicine, The University of Adelaide, Adelaide, South Australia 5005, Australia. School and Molecular and Biomedical Science, The University of Adelaide, Adelaide, South Australia 5005, Australia.
8
Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia.
9
Centre for Cancer Biology, an Alliance between SA Pathology and University of South Australia, Adelaide, South Australia 5000, Australia. Discipline of Biochemistry, School of Molecular and Biomedical Science, The University of Adelaide, Adelaide, South Australia 5005, Australia. Department of Medicine, The University of Adelaide, Adelaide, South Australia 5005, Australia. yeesim.khew-goodall@health.sa.gov.au.

Abstract

Factors secreted by tumor cells shape the local microenvironment to promote invasion and metastasis, as well as condition the premetastatic 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 by reducing intracellular protein trafficking through the secretory pathway. Knocking down PTPN14 in tumor cells or injecting the peritoneum of mice with conditioned medium from PTPN14-deficient cell cultures promoted the growth and metastasis of breast cancer xenografts. Loss of catalytically functional PTPN14 increased the secretion of growth factors and cytokines, such as IL-8 (interleukin-8), and increased the abundance of EGFR (epidermal growth factor receptor) at the cell surface of breast cancer cells and of FLT4 (vascular endothelial growth factor receptor 3) at the cell surface of primary lymphatic endothelial cells. We identified RIN1 (Ras and Rab interactor 1) and PRKCD (protein kinase C-δ) as binding partners and substrates of PTPN14. Similar to cells overexpressing PTPN14, receptor trafficking to the cell surface was inhibited in cells that lacked PRKCD or RIN1 or expressed a nonphosphorylatable RIN1 mutant, and cytokine secretion was decreased in cells treated with PRKCD inhibitors. Invasive breast cancer tissue had decreased expression of PTPN14, and patient survival was worse when tumors had increased expression of the genes encoding RIN1 or PRKCD. Thus, PTPN14 prevents metastasis by restricting the trafficking of both soluble and membrane-bound proteins.

PMID:
25690013
DOI:
10.1126/scisignal.2005547
[Indexed for MEDLINE]

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