The tyrosine phosphatase PTPN14 (Pez) inhibits metastasis by altering protein trafficking
| Autor: | Suraya Roslan, Roger J. Daly, Leila Belle, Paul Timpson, James R.W. Conway, Gelareh Farshid, Gregory J. Goodall, Freya Gehling, Yeesim Khew-Goodall, Xiaochun Li, Lesley A. Crocker, Naveid A. Ali, Anna Tsykin, David Herrmann, Andrew G. Bert, James L. Paltridge, Ana Lonic |
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| Přispěvatelé: | Belle, Leila, Ali, Naveid, Lonic, Ana, Li, Xiaochun, Paltridge, James L, Roslan, Suraya, Herrmann, David, Gehling, Freya K, Bert, Andrew G, Crocker, Lesley, Tsykin, Anna, Farshid, Gelareh, Goodall, Gregory J, Timpson, Paul, Daly, Roger, Khew-Goodall, Yeesim |
| Rok vydání: | 2015 |
| Předmět: |
cell-proliferation
Fluorescent Antibody Technique Protein tyrosine phosphatase growth-factor receptor Biochemistry Metastasis Mice Tandem Mass Spectrometry Tumor Microenvironment Epidermal growth factor receptor RIN1 Neoplasm Metastasis phosphorylation Intracellular Signaling Peptides and Proteins Protein Tyrosine Phosphatases Non-Receptor Protein Kinase C-delta Protein Transport PRKCD Gene Knockdown Techniques Isotope Labeling Cytokines Heterografts Intercellular Signaling Peptides and Proteins Female kinase-c-delta colorectal cancers Blotting Western epithelial-mesenchymal transition Breast Neoplasms Enzyme-Linked Immunosorbent Assay Biology Cell Line Tumor medicine tumor microenvironment Animals Humans Immunoprecipitation Secretion Neoplasm Invasiveness Molecular Biology breast-cancer Cell Biology medicine.disease FLT4 gene-expression Cell culture rab GTP-Binding Proteins Cancer research biology.protein Cytokine secretion Chromatography Liquid |
| Zdroj: | Science signaling. 8(364) |
| ISSN: | 1937-9145 |
| Popis: | 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-delta) 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. Refereed/Peer-reviewed |
| Databáze: | OpenAIRE |
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