title: Src Family Kinases Are Regulated in Multiple Myeloma Cells by Phosphatase of Regenerating Liver-3.
abstract: Phosphatase of regenerating liver-3 (PTP4A3/PRL-3) is a dual-specificity phosphatase that is upregulated in various types of cancers and is related to poor prognosis and aggressive tumor behavior. The expression level of PRL-3 is elevated in response to several antiapoptotic cytokines, including IL6, in cancer cells from patients with multiple myeloma (MM) and can promote survival and migration. Here, it is demonstrated that PRL-3 activates Src kinase in the IL6-dependent MM cell line INA-6. Inhibition of PRL-3 by a small-molecule inhibitor of PRL-3 or by shRNA resulted in inactivation of Src. In addition to activation of Src, PRL-3 also activated the Src family kinase (SFK) members LYN and HCK in INA-6 cells. Forced expression of catalytically inactive mutant PRL-3 decreased the activation of these three SFK members while the total level of HCK and FYN remained elevated. Inhibitors of Src increased sensitivity of cells overexpressing PRL-3 to the PRL-3 inhibitor through joint downregulation of both PRL-3 and Mcl-1. In conclusion, PRL-3 protected MM cells against apoptosis by dysregulating both the total levels and the activation levels of specific SFK members that are important for IL6 signal transduction in MM cells. Eventually, this led to increased levels of Mcl-1.
  
  
  
  This study suggests PRL-3 and SFKs are key mediators of the IL6-driven signaling events and points to both PRL-3 and SFK members as potential targets for treatment of MM. Mol Cancer Res; 15(1); 69-77. ©2016 AACR.
authors.affiliation: Department of Cancer Research and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway. pegah.abdollahi@ntnu.no.
authors.forename: Pegah
authors.initials: P
authors.lastname: Abdollahi
authors.affiliation: Department of Cancer Research and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Esten N
authors.initials: EN
authors.lastname: Vandsemb
authors.affiliation: Department of Cancer Research and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.|Department of Pediatrics, St. Olav's University Hospital, Trondheim, Norway.
authors.forename: Magnus A
authors.initials: MA
authors.lastname: Hjort
authors.affiliation: Department of Cancer Research and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Kristine
authors.initials: K
authors.lastname: Misund
authors.affiliation: Department of Cancer Research and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Toril
authors.initials: T
authors.lastname: Holien
authors.affiliation: Department of Cancer Research and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Anne-Marit
authors.initials: AM
authors.lastname: Sponaas
authors.affiliation: Department of Cancer Research and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.|Department of Pediatrics, St. Olav's University Hospital, Trondheim, Norway.
authors.forename: Torstein B
authors.initials: TB
authors.lastname: Rø
authors.affiliation: Department of Cancer Research and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.|Clinic of Medicine, St. Olav's University Hospital, Trondheim, Norway.
authors.forename: Tobias S
authors.initials: TS
authors.lastname: Slørdahl
authors.affiliation: Department of Cancer Research and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.|Department of Immunology and Transfusion Medicine, St. Olav's University Hospital, Norway.
authors.forename: Magne
authors.initials: M
authors.lastname: Børset
mesh_terms: D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002470:Cell Survival; D015536:Down-Regulation / Q000235:genetics; D004789:Enzyme Activation; D006801:Humans; D008954:Models, Biological; D009101:Multiple Myeloma / Q000201:enzymology* / Q000473:pathology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry / Q000378:metabolism*; D013997:Time Factors; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019000:Phosphotyrosine; D019061:src-Family Kinases; C484730:PTP4A3 protein, human; D017027:Protein Tyrosine Phosphatases