title: The kinases NDR1/2 act downstream of the Hippo homolog MST1 to mediate both egress of thymocytes from the thymus and lymphocyte motility.
abstract: The serine and threonine kinase MST1 is the mammalian homolog of Hippo. MST1 is a critical mediator of the migration, adhesion, and survival of T cells; however, these functions of MST1 are independent of signaling by its typical effectors, the kinase LATS and the transcriptional coactivator YAP. The kinase NDR1, a member of the same family of kinases as LATS, functions as a tumor suppressor by preventing T cell lymphomagenesis, which suggests that it may play a role in T cell homeostasis. We generated and characterized mice with a T cell-specific double knockout of Ndr1 and Ndr2 (Ndr DKO). Compared with control mice, Ndr DKO mice exhibited a substantial reduction in the number of naïve T cells in their secondary lymphoid organs. Mature single-positive thymocytes accumulated in the thymus in Ndr DKO mice. We also found that NDRs acted downstream of MST1 to mediate the egress of mature thymocytes from the thymus, as well as the interstitial migration of naïve T cells within popliteal lymph nodes. Together, our findings indicate that the kinases NDR1 and NDR2 function as downstream effectors of MST1 to mediate thymocyte egress and T cell migration.
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland. Department of Biomedicine, University of Basel, 4058 Basel, Switzerland. patrick.matthias@fmi.ch fengyuan.tang@fmi.ch.
authors.forename: Fengyuan
authors.initials: F
authors.lastname: Tang
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland.
authors.forename: Jason
authors.initials: J
authors.lastname: Gill
authors.affiliation: Theodor Kocher Institute, University of Bern, 3012 Bern, Switzerland.
authors.forename: Xenia
authors.initials: X
authors.lastname: Ficht
authors.affiliation: Laboratory of Pediatric Immunology, Department of Biomedicine, University of Basel and Basel University Children's Hospital, 4058 Basel, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Barthlott
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland.
authors.forename: Hauke
authors.initials: H
authors.lastname: Cornils
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland.
authors.forename: Debora
authors.initials: D
authors.lastname: Schmitz-Rohmer
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland.
authors.forename: Debby
authors.initials: D
authors.lastname: Hynx
authors.affiliation: State Key Laboratory of Stress Cell Biology, School of Life Sciences, Xiamen University, 361006 Xiamen, China.
authors.forename: Dawang
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland. Department of Biomedicine, University of Basel, 4058 Basel, Switzerland.
authors.forename: Gongda
authors.initials: G
authors.lastname: Xue
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland.
authors.forename: Michal
authors.initials: M
authors.lastname: Grzmil
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, 210061 Nanjing, China.
authors.forename: Zhongzhou
authors.initials: Z
authors.lastname: Yang
authors.affiliation: UCL Cancer Institute, WC1E 6BT London, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hergovich
authors.affiliation: Laboratory of Pediatric Immunology, Department of Biomedicine, University of Basel and Basel University Children's Hospital, 4058 Basel, Switzerland.
authors.forename: Georg A
authors.initials: GA
authors.lastname: Hollaender
authors.affiliation: Theodor Kocher Institute, University of Bern, 3012 Bern, Switzerland.
authors.forename: Jens V
authors.initials: JV
authors.lastname: Stein
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Hemmings
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland. Faculty of Science, University of Basel, 4003 Basel, Switzerland. patrick.matthias@fmi.ch fengyuan.tang@fmi.ch.
authors.forename: Patrick
authors.initials: P
authors.lastname: Matthias
mesh_terms: D000199:Actins / Q000502:physiology; D000818:Animals; D017209:Apoptosis; D002465:Cell Movement; D002633:Chemotaxis; D003599:Cytoskeleton / Q000648:ultrastructure; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000166:cytology*; D008221:Lymphoid Tissue / Q000473:pathology; D008231:Lymphopenia / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000166:cytology; D060168:Thymocytes / Q000166:cytology*; D013950:Thymus Gland / Q000473:pathology*; D057705:Transendothelial and Transepithelial Migration / Q000502:physiology*; D020741:rho GTP-Binding Proteins / Q000502:physiology; D000099317:Hippo Kinases
chemical_list: D000199:Actins; D017346:Protein Serine-Threonine Kinases; D020741:rho GTP-Binding Proteins; C490660:Stk4 protein, mouse; D000099317:Hippo Kinases; C552947:NDR1 protein kinase, mouse; C552948:NDR2 protein kinase, mouse