title: Mst1 Kinase Regulates the Actin-Bundling Protein L-Plastin To Promote T Cell Migration.
abstract: Exploring the mechanisms controlling lymphocyte trafficking is essential for understanding the function of the immune system and the pathophysiology of immunodeficiencies. The mammalian Ste20-like kinase 1 (Mst1) has been identified as a critical signaling mediator of T cell migration, and loss of Mst1 results in immunodeficiency disease. Although Mst1 is known to support T cell migration through induction of cell polarization and lamellipodial formation, the downstream effectors of Mst1 are incompletely defined. Mice deficient for the actin-bundling protein L-plastin (LPL) have phenotypes similar to mice lacking Mst1, including decreased T cell polarization, lamellipodial formation, and cell migration. We therefore asked whether LPL functions downstream of Mst1. The regulatory N-terminal domain of LPL contains a consensus Mst1 phosphorylation site at Thr(89) We found that Mst1 can phosphorylate LPL in vitro and that Mst1 can interact with LPL in cells. Removal of the Mst1 phosphorylation site by mutating Thr(89) to Ala impaired localization of LPL to the actin-rich lamellipodia of T cells. Expression of the T89A LPL mutant failed to restore migration of LPL-deficient T cells in vitro. Furthermore, expression of T89A LPL in LPL-deficient hematopoietic cells, using bone marrow chimeras, failed to rescue the phenotype of decreased thymic egress. These results identify LPL as a key effector of Mst1 and establish a novel mechanism linking a signaling intermediate to an actin-binding protein critical to T cell migration.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Xiaolu
authors.identifier: 0000-0002-9940-3605
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Xinxin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Todd
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Emily R
authors.initials: ER
authors.lastname: Jaeger
authors.affiliation: Department of Microbiology and Immunology, The Geisel School of Medicine at Dartmouth, Lebanon, NH 03756;
authors.forename: Jennifer L
authors.identifier: 0000-0002-6190-8114
authors.initials: JL
authors.lastname: Vella
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110; and.
authors.forename: Olivia L
authors.initials: OL
authors.lastname: Mooren
authors.affiliation: Department of Pathology, The Geisel School of Medicine at Dartmouth, Lebanon, NH 03756.
authors.forename: Yunfeng
authors.identifier: 0000-0001-9150-7795
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Jiancheng
authors.identifier: 0000-0003-1615-0030
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110; Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110; and.
authors.forename: John A
authors.identifier: 0000-0002-0933-4571
authors.initials: JA
authors.lastname: Cooper
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110; Division of Infectious Diseases, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110; morley_c@kids.wustl.edu yina.h.huang@dartmouth.edu.
authors.forename: Sharon Celeste
authors.identifier: 0000-0001-8424-0121
authors.initials: SC
authors.lastname: Morley
authors.affiliation: Department of Microbiology and Immunology, The Geisel School of Medicine at Dartmouth, Lebanon, NH 03756; Department of Pathology, The Geisel School of Medicine at Dartmouth, Lebanon, NH 03756 morley_c@kids.wustl.edu yina.h.huang@dartmouth.edu.
authors.forename: Yina H
authors.identifier: 0000-0002-0125-9351
authors.initials: YH
authors.lastname: Huang
mesh_terms: D000818:Animals; D002465:Cell Movement; D003598:Cytoskeletal Proteins; D005434:Flow Cytometry; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D008840:Microfilament Proteins; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D011554:Pseudopodia / Q000276:immunology / Q000502:physiology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D003598:Cytoskeletal Proteins; D008840:Microfilament Proteins; D010750:Phosphoproteins; C066559:Lcp1 protein, mouse; D017346:Protein Serine-Threonine Kinases