The Mst1 and Mst2 kinases control activation of rho family GTPases and thymic egress of mature thymocytes

Mou, Fan; Praskova, Maria; Xia, Fan; Buren, Denille Van; Hock, Hanno; Avruch, Joseph; Zhou, Dawang

doi:10.1084/jem.20111692

Cited by 142 publications

(139 citation statements)

References 49 publications

(86 reference statements)

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“…Mst1 − / − SP cells exhibited intact or mild affected chemotactic response to S1P, whereas CCL21/CCL19-dependent chemotaxis or migration on ICAM-1 was more severely affected 21,23 (this study). We speculate that defective migration of mature Mst1 − / − thymocytes triggered with chemokines and integrin ligands also affect egress processes.…”

Section: Discussionmentioning

confidence: 49%

“…Thymocyte egress in Mst1-deficient mice is also impaired, leading to a modest increase in mature thymocytes 20,21 . Double deficiencies of Mst1 and Mst2 result in more severe impairment of lymphocyte trafficking and thymocyte egress with enhanced apoptosis 23 . Mst1-deficient T cells exhibit TCR-induced hyperproliferative responses 24 , but this phenotype was not confirmed with other gene-targeted mice 21 .…”

mentioning

confidence: 99%

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Mst1 regulates integrin-dependent thymocyte trafficking and antigen recognition in the thymus

Ueda¹,

et al. 2012

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Thymocyte trafficking has an important role in thymic selection. Here we show that the Hippo homologue mst1 is required for thymocyte migration and antigen recognition by LFA-1 and ICAm-1 within the medulla. using two-photon imaging of thymic tissues, we found that highly motile mature thymocytes arrest and are activated in the vicinity of rare populations of Aire + ICAm-1 hi medullary thymic epithelia in a negatively selecting environment. notably, mst1 deficiency or blocking the cell adhesion molecules LFA-1 and ICAm-1 results in inefficient migration and antigen recognition of CD4 + thymocytes within the medulla. Consistent with these defects, thymocyte selection is impaired in Mst1 − / − mice, which display T cell-dependent inflammatory infiltrates in multiple organs and develop autoantibodies. our results suggest that mst1 has a key role in regulating thymocyte self-antigen recognition in the medulla.

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Section: Discussionmentioning

confidence: 49%

mentioning

confidence: 99%

Mst1 regulates integrin-dependent thymocyte trafficking and antigen recognition in the thymus

Ueda¹,

et al. 2012

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“…Both S1PR1/3 and S1PR2 inhibition exerted a similar effect on MHCII and CD40 expression. Because different intracellular GTPases are activated by S1PR1/3 or S1PR2 ligation, these findings suggest that not only one receptor or intracellular signaling pathway is involved (49)(50)(51).…”

Section: Discussionmentioning

confidence: 92%

Low Sphingosine-1–Phosphate Impairs Lung Dendritic Cells in Cystic Fibrosis

Krause

Limberis

et al. 2013

Am J Respir Cell Mol Biol

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Dysfunction of the cystic fibrosis transmembrane regulator (CFTR) leads to chronic inflammation and infection of the respiratory tract. The role of CFTR for cells of the pulmonary immune system is only partly understood. The present study analyzes the phenotype and immune stimulatory capacity of lung dendritic cells (DCs) from CFTR knockout (CF) mice. Total numbers of conventional DCs, plasmacytoid DCs, and CD103-positive DCs were lower in CF mice compared with wild-type (WT) control mice, as was the expression of major histocompatibility complex class II molecules (MHCII), CD40, and CD86. After pulmonary infection with respiratory syncytial virus, DC numbers increased in WT mice but not in CF mice, and the T cellstimulatory capacity of CF DCs was impaired. The culture of CF lung DCs with bronchoalveolar lavage fluid (BALF) from WT mice increased the expression of MHCII, CD40, and CD86. The supplementation of CF BALF with sphingosine-1-phosphate (S1P), a mediator of immune cell migration and activation that is decreased in CF BALF, rescued the reduced expression of MHCII and CD40 in WT lung DCs and human blood DCs. These findings suggest that DCs are impaired in the CF lung, and that altered S1P affects lung DC function. These findings provide a novel link between defective CFTR and pulmonary innate immune dysfunction in CF.

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“…[18][19][20][21][22][23] MST1 has been implicated in T-cell biology, as mice lacking MST1 exhibit a variety of T-cell abnormalities. 24 Cross-talk between MST1 and Akt appears able to antagonize Akt1 activity, 25 which is involved in T-cell costimulation and the regulation of NF-kB-dependent gene transcription. MST1 negatively regulates the activation and proliferative response of naive T cells.…”

Section: Gck-ii Kinases Regulate Lymphocyte Adhesion Migration Prolmentioning

confidence: 99%

“…32 MST1/2 may control Rho GTPase activation and mature T cells egress from the thymus by activating Dock8. 24 In MST1 and MST2 double knockout mice, mature T cells cannot efficiently migrate from thymus to the circulation and secondary lymphoid organs. While T cells can develop normally in these double knockout mice, the apoptotic rate of CD4 1 CD8 2 and CD4 2 CD8 1 single-positive thymocytes is dramatically increased.…”

Section: Gck-ii Kinases Regulate Lymphocyte Adhesion Migration Prolmentioning

confidence: 99%

Germinal center kinases in immune regulation

Yin

Shi

et al. 2012

Cell Mol Immunol

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The Mst1 and Mst2 kinases control activation of rho family GTPases and thymic egress of mature thymocytes

Abstract: In mice lacking both Mst1 and Mst2 in the lymphoid compartment, thymocyte development is normal, but single-positive thymocytes exhibit excessive apoptosis and greatly diminished thymic egress, accompanied by loss of chemokine activation of RhoA and Rac1.

Cited by 142 publications

References 49 publications

Mst1 regulates integrin-dependent thymocyte trafficking and antigen recognition in the thymus

Mst1 regulates integrin-dependent thymocyte trafficking and antigen recognition in the thymus

Low Sphingosine-1–Phosphate Impairs Lung Dendritic Cells in Cystic Fibrosis

Germinal center kinases in immune regulation

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