Notch-induced T cell development requires phosphoinositide-dependent kinase 1

被引:110
作者
Kelly, April P.
Finlay, David K.
Hinton, Heather J.
Clarke, Rosie G.
Fiorini, Emma
Radtke, Freddy
Cantrell, Doreen A.
机构
[1] Univ Dundee, Div Cell Biol & Immunol, Coll Life Sci, Dundee DD1 5EH, Scotland
[2] Ctyos Biotechnol AG, Zurich, Switzerland
[3] Univ Lausanne, Ludwig Inst Canc Res, CH-1066 Epalinges, Switzerland
[4] Ecole Polytech Fed Lausanne, Dept Life Sci, Swiss Inst Expt Canc Res, Epalinges, Switzerland
基金
英国惠康基金;
关键词
notch; PDK1; PKB; RSK; thymus;
D O I
10.1038/sj.emboj.7601761
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Phosphoinositide-dependent kinase l (PDK1) phosphorylates and activates multiple AGC serine kinases, including protein kinase B (PKB), p70Ribosomal S6 kinase (S6K) and p90Ribosomal S6 kinase (RSK). PDK1 is required for thymocyte differentiation and proliferation, and herein, we explore the molecular basis for these essential functions of PDK1 in T lymphocyte development. A key finding is that PDK1 is required for the expression of key nutrient receptors in T cell progenitors: CD71 the transferrin receptor and CD98 a subunit of L-amino acid transporters. PDK1 is also essential for Notch-mediated trophic and proliferative responses in thymocytes. A PDK1 mutant PDK1 L155E, which supports activation of PKB but no other AGC kinases, can restore CD71 and CD98 expression in pre-T cells and restore thymocyte differentiation. However, PDK1 L155E is insufficient for thymocyte proliferation. The role of PDK1 in thymus development thus extends beyond its ability to regulate PKB. In addition, PDK1 phosphorylation of AGC kinases such as S6K and RSK is also necessary for thymocyte development.
引用
收藏
页码:3441 / 3450
页数:10
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