The Nore1B/Mst1 complex restrains antigen receptor-induced proliferation of naïve T cells.
The Mst1 and Mst2 protein kinases are the mammalian homologs of hippo, a major inhibitor of cell proliferation in Drosophila. Mst1 is most abundant in lymphoid tissues. Mice lacking Mst1 exhibit markedly reduced levels of the Mst1 regulatory protein Nore1B/RAPL in lymphoid cells, whereas Mst2 abundance is unaltered. Mst1-null mice exhibit normal T cell development but low numbers of mature naïve T cells with relatively normal numbers of effector/memory T cells. In vitro, the Mst1-deficient naïve T cells exhibit markedly greater proliferation in response to stimulation of the T cell receptor whereas the proliferative responses of the Mst1-null effector/memory T cell cohort is similar to wild type. Thus, elimination of Mst1 removes a barrier to the activation and proliferative response of naïve T cells. The levels of Mst1 and Nore1B/RAPL in wild-type effector/memory T cells are approximately 10% those seen in wild-type naïve T cells, which may contribute to the enhanced proliferative responses of the former. Freshly isolated Mst1-null T cells exhibit high rates of ongoing apoptosis, a likely basis for their low numbers in vivo; they also exhibit defective clustering of LFA-1, as previously observed for Nore1B/RAPL-deficient T cells. Among known Mst1 substrates, only the phosphorylation of the cell cycle inhibitory proteins MOBKL1A/B is lost entirely in TCR-stimulated, Mst1-deficient T cells. Mst1/2-catalyzed MOBKL1A/B phosphorylation slows proliferation and is therefore a likely contributor to the anti-proliferative action of Mst1 in naïve T cells. The Nore1B/RAPL-Mst1 complex is a negative regulator of naïve T cell proliferation.
Zhou
Dawang
D
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
Medoff
Benjamin D
BD
Chen
Lanfen
L
Li
Lequn
L
Zhang
Xian-feng
XF
Praskova
Maria
M
Liu
Matthew
M
Landry
Aimee
A
Blumberg
Richard S
RS
Boussiotis
Vassiliki A
VA
Xavier
Ramnik
R
Avruch
Joseph
J
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D049109:Cell Proliferation; D008213:Lymphocyte Activation; D051379:Mice; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology*; D000099317:Hippo Kinases
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011948:Receptors, Antigen, T-Cell; C529494:Mob1b protein, mouse; C455831:Rassf5 protein, mouse; C490660:Stk4 protein, mouse; D000099317:Hippo Kinases