Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/99803
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Type: Journal article
Title: The tyrosine phosphatase PTPN14 (Pez) inhibits metastasis by altering protein trafficking
Author: Belle, L.
Ali, N.
Lonic, A.
Li, X.
Paltridge, J.
Roslan, S.
Herrmann, D.
Conway, J.
Gehling, F.
Bert, A.
Crocker, L.
Tsykin, A.
Farshid, G.
Goodall, G.
Timpson, P.
Daly, R.
Khew-Goodall, Y.
Citation: Science Signaling, 2015; 8(364):ra18-1-ra18-12
Publisher: American Association for the Advancement of Science
Issue Date: 2015
ISSN: 1945-0877
1937-9145
Statement of
Responsibility: 
Leila Belle, Naveid Ali, Ana Lonic, Xiaochun Li, James L. Paltridge, Suraya Roslan, David Herrmann, James R. W. Conway, Freya K. Gehling, Andrew G. Bert, Lesley A. Crocker, Anna Tsykin, Gelareh Farshid, Gregory J. Goodall, Paul Timpson, Roger J. Daly, and Yeesim Khew-Goodall
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-╬┤) 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.
Keywords: Neoplasm Invasiveness; Neoplasm Metastasis; rab GTP-Binding Proteins
Rights: Copyright status unknown
RMID: 0030025542
DOI: 10.1126/scisignal.2005547
Grant ID: http://purl.org/au-research/grants/nhmrc/626918
http://purl.org/au-research/grants/nhmrc/535903
http://purl.org/au-research/grants/nhmrc/535914
Appears in Collections:Molecular and Biomedical Science publications

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