title: The Mst1 and Mst2 kinases control activation of rho family GTPases and thymic egress of mature thymocytes.
abstract: The Mst1 kinase is an important regulator of murine T cell adhesion, migration, proliferation, and apoptosis. In this study, we analyze mice lacking both Mst1 and Mst2 in hematopoietic cells. Compared with wild-type mice, these double knockout (DKO) mice exhibit a severe reduction in the number of mature T cells in the circulation and in secondary lymphoid organs (SLOs). CD4(+)CD8(-) and CD4(-)CD8(+) single-positive (SP) thymocytes in DKO mice resemble mature T cells of wild-type mice but undergo excessive apoptosis, and their egress from the thymus is reduced by >90%. Even when placed directly in the circulation, DKO SP thymocytes failed to enter SLOs. In SP thymocytes, deficiency of Mst1 and Mst2 abolished sphingosine-1 phosphate- and CCL21-induced Mob1 phosphorylation, Rac1 and RhoA GTP charging, and subsequent cell migration. When phosphorylated by Mst1 or Mst2, Mob1 binds and activates the Rac1 guanyl nucleotide exchanger Dock8, which is abundant in the thymus. Thus, the Mst1 and Mst2 kinases control Rho GTPase activation and the migratory responses of SP thymocytes.
authors.affiliation: Department of Molecular Biology, Massachusetts GeneralHospital, Boston, MA 02114, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Mou
authors.forename: Maria
authors.initials: M
authors.lastname: Praskova
authors.forename: Fan
authors.initials: F
authors.lastname: Xia
authors.forename: Denille
authors.initials: D
authors.lastname: Van Buren
authors.forename: Hanno
authors.initials: H
authors.lastname: Hock
authors.forename: Joseph
authors.initials: J
authors.lastname: Avruch
authors.forename: Dawang
authors.initials: D
authors.lastname: Zhou
mesh_terms: D000199:Actins / Q000737:chemistry; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement; D002633:Chemotaxis; D004789:Enzyme Activation; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D000090742:Serine-Threonine Kinase 3; D060168:Thymocytes / Q000502:physiology*; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D000099317:Hippo Kinases
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D017228:Hepatocyte Growth Factor; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000090742:Serine-Threonine Kinase 3; D020741:rho GTP-Binding Proteins; C529494:Mob1b protein, mouse; C082332:macrophage stimulating protein; C490818:Stk3 protein, mouse; D000099317:Hippo Kinases