The serine kinase phosphoinositide-dependent kinase 1 (PDK1) regulates T cell development.
T lymphocyte activation is associated with activation of diverse AGC serine kinases (named after family members protein kinase A, protein kinase G and protein kinase C). It has been difficult to assess the function of these molecules in T cell development with simple gene-deletion strategies because different isoforms of AGC kinases are coexpressed in the thymus and have overlapping, redundant functions. To circumvent these problems, we explored the consequences of genetic manipulation of phosphoinositide-dependent kinase 1 (PDK1), a rate-limiting 'upstream' activator of AGC kinases. Here we analyzed the effect of PDK1 deletion on T lineage development. We also assessed the consequences of reducing PDK1 levels to 10% of normal. Complete PDK1 loss blocked T cell differentiation in the thymus, whereas reduced PDK1 expression allowed T cell differentiation but blocked proliferative expansion. These studies show that AGC family kinases are essential for T cell development.
Hinton
Heather J
HJ
Lymphocyte Activation Laboratory, Cancer Research UK London Research Institute, Lincoln's Inn Fields, London WC2A 3PX, United Kingdom.
Alessi
Dario R
DR
Cantrell
Doreen A
DA
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D017353:Gene Deletion; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics / Q000502:physiology; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology*; D013950:Thymus Gland / Q000502:physiology; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
D014764:Viral Proteins; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D064413:3-Phosphoinositide-Dependent Protein Kinases; C578564:Pdpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; C045073:Cre recombinase; D019426:Integrases