Notch-induced T cell development requires phosphoinositide-dependent kinase 1.
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.
Kelly
April P
AP
College of Life Science, Division of Cell Biology & Immunology, MSI/WTB complex, University of Dundee, Dundee, UK.
Finlay
David K
DK
Hinton
Heather J
HJ
Clarke
Rosie G
RG
Fiorini
Emma
E
Radtke
Freddy
F
Cantrell
Doreen A
DA
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005502:Food; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D058570:TOR Serine-Threonine Kinases
D050505:Mutant Proteins; D047428:Protein Kinase Inhibitors; D051880:Receptors, Notch; D011494:Protein Kinases; C546843:mTOR protein, mouse; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578564:Pdpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases