title: The tyrosine phosphatase PTPN14 (Pez) inhibits metastasis by altering protein trafficking.
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.
authors.affiliation: 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.
authors.forename: Leila
authors.initials: L
authors.lastname: Belle
authors.affiliation: Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.
authors.forename: Naveid
authors.initials: N
authors.lastname: Ali
authors.affiliation: 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.
authors.forename: Ana
authors.initials: A
authors.lastname: Lonic
authors.affiliation: Centre for Cancer Biology, an Alliance between SA Pathology and University of South Australia, Adelaide, South Australia 5000, Australia.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Li
authors.affiliation: 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.
authors.forename: James L
authors.initials: JL
authors.lastname: Paltridge
authors.affiliation: Centre for Cancer Biology, an Alliance between SA Pathology and University of South Australia, Adelaide, South Australia 5000, Australia.
authors.forename: Suraya
authors.initials: S
authors.lastname: Roslan
authors.affiliation: Cancer Research Program, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Herrmann
authors.affiliation: Cancer Research Program, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.
authors.forename: James R W
authors.initials: JR
authors.lastname: Conway
authors.affiliation: Centre for Cancer Biology, an Alliance between SA Pathology and University of South Australia, Adelaide, South Australia 5000, Australia.
authors.forename: Freya K
authors.initials: FK
authors.lastname: Gehling
authors.affiliation: Centre for Cancer Biology, an Alliance between SA Pathology and University of South Australia, Adelaide, South Australia 5000, Australia.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Bert
authors.affiliation: Centre for Cancer Biology, an Alliance between SA Pathology and University of South Australia, Adelaide, South Australia 5000, Australia.
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Crocker
authors.affiliation: Centre for Cancer Biology, an Alliance between SA Pathology and University of South Australia, Adelaide, South Australia 5000, Australia.
authors.forename: Anna
authors.initials: A
authors.lastname: Tsykin
authors.affiliation: Division of Tissue Pathology, SA Pathology, Adelaide, South Australia 5000, Australia.
authors.forename: Gelareh
authors.initials: G
authors.lastname: Farshid
authors.affiliation: 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.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Goodall
authors.affiliation: Cancer Research Program, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Timpson
authors.affiliation: 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.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Daly
authors.affiliation: 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.
authors.forename: Yeesim
authors.initials: Y
authors.lastname: Khew-Goodall
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002853:Chromatography, Liquid; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D064593:Heterografts / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D047468:Immunoprecipitation; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D007553:Isotope Labeling; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis / Q000503:physiopathology* / Q000517:prevention & control; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology*; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D053719:Tandem Mass Spectrometry; D059016:Tumor Microenvironment / Q000502:physiology*; D020691:rab GTP-Binding Proteins / Q000378:metabolism
chemical_list: D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C490451:Rin1 protein, mouse; C497259:Prkcd protein, mouse; D051745:Protein Kinase C-delta; C573780:PTPN14 protein, mouse; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D020691:rab GTP-Binding Proteins