title: ErbB2, EphrinB1, Src kinase and PTPN13 signaling complex regulates MAP kinase signaling in human cancers.
abstract: In non-cancerous cells, phosphorylated proteins exist transiently, becoming de-phosphorylated by specific phosphatases that terminate propagation of signaling pathways. In cancers, compromised phosphatase activity and/or expression occur and contribute to tumor phenotype. The non-receptor phosphatase, PTPN13, has recently been dubbed a putative tumor suppressor. It decreased expression in breast cancer correlates with decreased overall survival. Here we show that PTPN13 regulates a new signaling complex in breast cancer consisting of ErbB2, Src, and EphrinB1. To our knowledge, this signaling complex has not been previously described. Co-immunoprecipitation and localization studies demonstrate that EphrinB1, a PTPN13 substrate, interacts with ErbB2. In addition, the oncogenic V660E ErbB2 mutation enhances this interaction, while Src kinase mediates EphrinB1 phosphorylation and subsequent MAP Kinase signaling. Decreased PTPN13 function further enhances signaling. The association of oncogene kinases (ErbB2, Src), a signaling transmembrane ligand (EphrinB1) and a phosphatase tumor suppressor (PTPN13) suggest that EphrinB1 may be a relevant therapeutic target in breast cancers harboring ErbB2-activating mutations and decreased PTPN13 expression.
authors.affiliation: Cancer Biology Research Center, Sanford Research/University of South Dakota, Sioux Falls, South Dakota, United States of America.
authors.forename: Paola D
authors.initials: PD
authors.lastname: Vermeer
authors.forename: Megan
authors.initials: M
authors.lastname: Bell
authors.forename: Kimberly
authors.initials: K
authors.lastname: Lee
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Vermeer
authors.forename: Byrant G
authors.initials: BG
authors.lastname: Wieking
authors.forename: Erhan
authors.initials: E
authors.lastname: Bilal
authors.forename: Gyan
authors.initials: G
authors.lastname: Bhanot
authors.forename: Ronny I
authors.initials: RI
authors.lastname: Drapkin
authors.forename: Shridar
authors.initials: S
authors.lastname: Ganesan
authors.forename: Aloysius J
authors.initials: AJ
authors.lastname: Klingelhutz
authors.forename: Wiljan J
authors.initials: WJ
authors.lastname: Hendriks
authors.forename: John H
authors.initials: JH
authors.lastname: Lee
mesh_terms: D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D036387:Ephrin-B1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D011485:Protein Binding; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D036387:Ephrin-B1; D020928:Mitogen-Activated Protein Kinases; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13; D018719:Erb-b2 Receptor Tyrosine Kinases; D019061:src-Family Kinases; C484288:EFNB1 protein, human; C516742:PTPN13 protein, human