Research ArticleImmunology

The kinases NDR1/2 act downstream of the Hippo homolog MST1 to mediate both egress of thymocytes from the thymus and lymphocyte motility

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Sci. Signal.  06 Oct 2015:
Vol. 8, Issue 397, pp. ra100
DOI: 10.1126/scisignal.aab2425

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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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