title: Caspase Cleavages of the Lymphocyte-oriented Kinase Prevent Ezrin, Radixin, and Moesin Phosphorylation during Apoptosis.
abstract: The lymphocyte-oriented kinase (LOK), also called serine threonine kinase 10 (STK10), is synthesized mainly in lymphocytes. It is involved in lymphocyte migration and polarization and can phosphorylate ezrin, radixin, and moesin (the ERM proteins). In a T lymphocyte cell line and in purified human lymphocytes, we found LOK to be cleaved by caspases during apoptosis. The first cleavage occurs at aspartic residue 332, located between the kinase domain and the coiled-coil regulation domain. This cleavage generates an N-terminal fragment, p50 N-LOK, containing the kinase domain and a C-terminal fragment, which is further cleaved during apoptosis. Although these cleavages preserve the entire kinase domain, p50 N-LOK displays no kinase activity. In apoptotic lymphocytes, caspase cleavages of LOK are concomitant with a decrease in ERM phosphorylation. When non-apoptotic lymphocytes from mice with homozygous and heterozygous LOK knockout were compared, the latter showed a higher level of ERM phosphorylation, but when apoptosis was induced, LOK(-/-) and LOK(+/-) lymphocytes showed the same low level, confirming in vivo that LOK-induced ERM phosphorylation is prevented during lymphocyte apoptosis. Our results demonstrate that cleavage of LOK during apoptosis abolishes its kinase activity, causing a decrease in ERM phosphorylation, crucial to the role of the ERM proteins in linking the plasma membrane to actin filaments.
authors.affiliation: From the University of Lille, CNRS, Institut Pasteur de Lille, Unité Mixte de Recherche (UMR) 8161, Mechanisms of Tumorigenesis and Target Therapies, 59000 Lille, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Leroy
authors.affiliation: the Thoracic and Gastrointestinal Oncology and.
authors.forename: Natalya V
authors.initials: NV
authors.lastname: Belkina
authors.affiliation: the University of Lille, CNRS, INSERM, Centre Hospitalier Régional Universitaire de Lille, Institut Pasteur de Lille, U1019-UMR 8204, Center for Infection and Immunity of Lille, 59000 Lille, France.
authors.forename: Thavy
authors.initials: T
authors.lastname: Long
authors.affiliation: the University of Lille, CNRS, INSERM, Centre Hospitalier Régional Universitaire de Lille, Institut Pasteur de Lille, U1019-UMR 8204, Center for Infection and Immunity of Lille, 59000 Lille, France.
authors.forename: Emeric
authors.initials: E
authors.lastname: Deruy
authors.affiliation: the University of Lille, CNRS, INSERM, Centre Hospitalier Régional Universitaire de Lille, Institut Pasteur de Lille, U1019-UMR 8204, Center for Infection and Immunity of Lille, 59000 Lille, France.
authors.forename: Colette
authors.initials: C
authors.lastname: Dissous
authors.affiliation: Experimental Immunology Branch Branches, NCI/National Institutes of Health, Bethesda, Maryland 20892, and.
authors.forename: Stephen
authors.initials: S
authors.lastname: Shaw
authors.affiliation: From the University of Lille, CNRS, Institut Pasteur de Lille, Unité Mixte de Recherche (UMR) 8161, Mechanisms of Tumorigenesis and Target Therapies, 59000 Lille, France.
authors.forename: David
authors.initials: D
authors.lastname: Tulasne
mesh_terms: D000199:Actins / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism*; D002462:Cell Membrane; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008214:Lymphocytes / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism* / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D000099149:Ezrin
chemical_list: D000199:Actins; D020169:Caspases; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D000099149:Ezrin; C071058:moesin; C071776:radixin; C474806:STK10 protein, human; C108145:Stk10 protein, mouse
keywords: STK10; apoptosis; caspase; cell signaling; ezrin; lymphocyte-oriented kinase; moesin; protein kinase; radixin