title: PRL-3 mediates the protein maturation of ULBP2 by regulating the tyrosine phosphorylation of HSP60.
abstract: Many malignant cells release the NKG2D ligand ULBP2 from their cell surface to evade immunosurveillance by NK cells and CD8 T cells. Although the shedding mechanism remains unclear, various inhibitors of matrix metalloproteinases have been shown to efficiently block the release of soluble ULBP2. The clinical use of these inhibitors, however, is limited because of adverse side effects. Using high-throughput screening technique, we identified a specific inhibitor of phosphatase of regenerating liver 3 (PRL-3) that could reduce the level of soluble ULBP2 in the culture supernatant of various cancer cell lines. Inhibition or gene knockdown of PRL-3 did not reduce ULBP2 shedding, but rather suppressed posttranslational maturation of ULBP2, resulting in intracellular retention of immature ULBP2. We then found that ULBP2 was constitutively associated with heat shock protein HSP60. Complete maturation of ULBP2 required tyrosine phosphorylation of HSP60 which was mediated by PRL-3.
authors: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105;
authors: Wai-Hang
authors: WH
authors: Leung
authors: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105;
authors: Queenie P
authors: QP
authors: Vong
authors: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105; and.
authors: Wenwei
authors: W
authors: Lin
authors: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105; and.
authors: David
authors: D
authors: Bouck
authors: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105;
authors: Susanne
authors: S
authors: Wendt
authors: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105;
authors: Erin
authors: E
authors: Sullivan
authors: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105;
authors: Ying
authors: Y
authors: Li
authors: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105;
authors: Rafijul
authors: R
authors: Bari
authors: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105; and.
authors: Taosheng
authors: T
authors: Chen
authors: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105; Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38103 wing.leung@stjude.org.
authors: Wing
authors: W
authors: Leung
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018834:Chaperonin 60 / Q000276:immunology* / Q000378:metabolism; D004151:Dipeptides / Q000276:immunology / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000276:immunology / Q000494:pharmacology; D058851:GPI-Linked Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D045325:HCT116 Cells; D057809:HEK293 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000276:immunology / Q000494:pharmacology; D018613:Microscopy, Confocal; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014443:Tyrosine / Q000276:immunology / Q000378:metabolism
chemical_list: D018834:Chaperonin 60; D004151:Dipeptides; D004791:Enzyme Inhibitors; D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D009363:Neoplasm Proteins; C423230:ULBP2 protein, human; D014443:Tyrosine; C484730:PTP4A3 protein, human; D017027:Protein Tyrosine Phosphatases