title: Mst1 directs Myosin IIa partitioning of low and higher affinity integrins during T cell migration.
abstract: Chemokines promote T cell migration by transmitting signals that induce T cell polarization and integrin activation and adhesion. Mst1 kinase is a key signal mediator required for both of these processes; however, its molecular mechanism remains unclear. Here, we present a mouse model in which Mst1 function is disrupted by a hypomorphic mutation. Microscopic analysis of Mst1-deficient CD4 T cells revealed a necessary role for Mst1 in controlling the localization and activity of Myosin IIa, a molecular motor that moves along actin filaments. Using affinity specific LFA-1 antibodies, we identified a requirement for Myosin IIa-dependent contraction in the precise spatial distribution of low and higher affinity LFA-1 on the membrane of migrating T cells. Mst1 deficiency or Myosin inhibition resulted in multipolar cells, difficulties in uropod detachment and mis-localization of low affinity LFA-1. Thus, Mst1 regulates Myosin IIa dynamics to organize high and low affinity LFA-1 to the anterior and posterior membrane during T cell migration.
authors.affiliation: Department of Pathology and Immunology, Washington University, St. Louis, Missouri, United States of America.
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Pathology and Immunology, Washington University, St. Louis, Missouri, United States of America.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Jaeger
authors.affiliation: Department of Pathology and Immunology, Washington University, St. Louis, Missouri, United States of America.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California, United States of America.
authors.forename: Erica
authors.initials: E
authors.lastname: Lagler-Ferrez
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California, United States of America.
authors.forename: Serge
authors.initials: S
authors.lastname: Batalov
authors.affiliation: Department of Pathology and Immunology, Washington University, St. Louis, Missouri, United States of America.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Mathis
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Tim
authors.initials: T
authors.lastname: Wiltshire
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California, United States of America.
authors.forename: John R
authors.initials: JR
authors.lastname: Walker
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California, United States of America.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Cooke
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Karsten
authors.initials: K
authors.lastname: Sauer
authors.affiliation: Department of Pathology and Immunology, Washington University, St. Louis, Missouri, United States of America; Departments of Pathology and Microbiology & Immunology, The Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States of America.
authors.forename: Yina H
authors.initials: YH
authors.lastname: Huang
mesh_terms: D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D054415:Chemokine CCL19 / Q000276:immunology; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000276:immunology*; D016023:Integrins / Q000276:immunology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology; D008810:Mice, Inbred C57BL; D009154:Mutation; D024507:Nonmuscle Myosin Type IIA / Q000276:immunology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism
chemical_list: D054415:Chemokine CCL19; D016023:Integrins; D016169:Lymphocyte Function-Associated Antigen-1; D011518:Proto-Oncogene Proteins; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor; D024507:Nonmuscle Myosin Type IIA