title: Pericentrosomal localization of the TIG3 tumor suppressor requires an N-terminal hydrophilic region motif.
abstract: Tazarotene-induced gene 3 (TIG3) is a tumor suppressor protein that has a key role in controlling cell proliferation. TIG3 is observed at reduced levels in epidermal squamous cell carcinoma, and the restoration of expression in skin cancer cells reduces cell survival. TIG3 suppresses cell survival through mechanisms that involve localization at the plasma membrane and at the centrosome. TIG3 interacts at the plasma membrane to activate enzymes involved in keratinocyte terminal differentiation, and at the centrosome to inhibit daughter centrosome separation during mitosis leading to cessation of cell proliferation and induction of apoptosis. An important goal is identifying the motifs required for TIG3 localization at these intracellular sites as a method to understand the function of TIG3 at each location. TIG3 encodes an N-terminal hydrophilic region (amino acids 1-135) and a C-terminal membrane-anchoring domain (amino acids 135-164). We show that the C-terminal hydrophobic domain targets intact TIG3 to the plasma membrane, but when isolated as an independent element localizes at the mitochondria. We further demonstrate that a segment of the N-terminal hydrophilic region targets the centrosome. These studies provide important insights regarding the mechanisms that guide subcellular localization of this keratinocyte survival regulator.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Tiffany M
authors.initials: TM
authors.lastname: Scharadin
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Gautam
authors.initials: G
authors.lastname: Adhikary
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Kristin
authors.initials: K
authors.lastname: Shaw
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Dan J B
authors.initials: DJB
authors.lastname: Grun
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA; Department of Dermatology, University of Maryland School of Medicine, Baltimore, Maryland, USA; Department of Obstetrics and Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, Maryland, USA. Electronic address: reckert@umaryland.edu.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Eckert
mesh_terms: D017209:Apoptosis / Q000502:physiology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D018385:Centrosome / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D000078404:Epidermal Cells; D004817:Epidermis / Q000502:physiology; D016147:Genes, Tumor Suppressor / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D021381:Protein Transport / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology
chemical_list: C437968:PLAAT4 protein, human; D018168:Receptors, Retinoic Acid; D049452:Green Fluorescent Proteins