The kinases NDR1/2 act downstream of the Hippo homolog MST1 to mediate both egress of thymocytes from the thymus and lymphocyte motility
Sending thymocytes into action
MST1, the mammalian homolog of Hippo, plays a role in apoptosis and cellular proliferation by activating the kinase LATS, which inhibits the transcriptional coactivator YAP; however, MST1 also functions independently of LATS and YAP in T cell adhesion and migration. Tang et al. generated mice with a T cell–specific deficiency in both isoforms of the LATS-related kinase NDR. These mice had reduced numbers of naïve T cells in the periphery because mature thymocytes were trapped in the thymus. Chemoattractants stimulated actin polymerization and the migration of thymocytes in an MST1- and NDR-dependent manner, suggesting that the NDRs act downstream of MST1 to mediate thymocyte egress.
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.
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Supplementary Material
Summary
Fig. S1. Analysis of T cell apoptosis, proliferation, and T cell subsets in wild-type and Ndr DKO mice.
Fig. S2. Analysis of thymocyte proliferation and measurement of body and spleen weights of wild-type and Ndr DKO mice.
Fig. S3. Loss of NDRs results in the accumulation of mature SP thymocytes in the perivascular space of the thymus.
Fig. S4. Loss of NDRs does not impair the homing of naïve T cells to lymphoid organs.
Fig. S5. Biochemical analysis of MST-NDR signaling in T cells.
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Published In
Science Signaling
Volume 8 | Issue 397
October 2015
October 2015
Copyright
Copyright © 2015, American Association for the Advancement of Science.
Submission history
Received: 31 March 2015
Accepted: 18 September 2015
Acknowledgments
We thank H. Kohler for help with the flow cytometric analysis, G. Christofori and N. Hynes for support, the Friedrich Miescher Institute (FMI) Microscopy facility for help with imaging, M. Stadler for help with statistical analysis, and W. van Ewijk for the ER-TR7 antibody. Funding: F.T. and D.S.-R. were supported by the Swiss National Science Foundation SNF 31003A_138287; J.G. was supported by the Swiss Cancer League KFS 02743-02-2011; G.X. was funded by the Swiss National Science Foundation SNF 31003A_130838, and A.H. is a Wellcome Trust Research Career Development fellow (grant 090090/Z/09/Z). The FMI for Biomedical Research is supported by the Novartis Research Foundation. Author contributions: B.A.H., P.M., and F.T. conceived this project; F.T. designed the study, analyzed the data, and wrote the manuscript; J.G., X.F., J.V.S., T.B., and G.A.H. designed the experiments, analyzed the data, and participated in manuscript preparation; H.C. generated the Ndr DKO mice for preliminary analysis; D.S.-R. provided Ndr2f/f mice; D.H. helped with mouse management; D.Z. provided Mst1 KO mouse samples; L.Z., G.X., M.G., and Z.Y. helped with experiments and provided fruitful discussion; and A.H. and P.M. participated in manuscript preparation. Competing interests: The authors declare that they have no competing interests.
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