title: Phosphoinositide-dependent kinase 1 controls migration and malignant transformation but not cell growth and proliferation in PTEN-null lymphocytes.
abstract: In normal T cell progenitors, phosphoinositide-dependent kinase l (PDK1)-mediated phosphorylation and activation of protein kinase B (PKB) is essential for the phosphorylation and inactivation of Foxo family transcription factors, and also controls T cell growth and proliferation. The current study has characterized the role of PDK1 in the pathology caused by deletion of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN). PDK1 is shown to be essential for lymphomagenesis caused by deletion of PTEN in T cell progenitors. However, PTEN deletion bypasses the normal PDK1-controlled signaling pathways that determine thymocyte growth and proliferation. PDK1 does have important functions in PTEN-null thymocytes, notably to control the PKB-Foxo signaling axis and to direct the repertoire of adhesion and chemokine receptors expressed by PTEN-null T cells. The results thus provide two novel insights concerning pathological signaling caused by PTEN loss in lymphocytes. First, PTEN deletion bypasses the normal PDK1-controlled metabolic checkpoints that determine cell growth and proliferation. Second, PDK1 determines the cohort of chemokine and adhesion receptors expressed by PTEN-null cells, thereby controlling their migratory capacity.
authors.affiliation: Division of Immunology and Cell Biology, University of Dundee, Dundee DD15EH, Scotland, UK.
authors.forename: David K
authors.initials: DK
authors.lastname: Finlay
authors.forename: Linda V
authors.initials: LV
authors.lastname: Sinclair
authors.forename: Carmen
authors.initials: C
authors.lastname: Feijoo
authors.forename: Caryll M
authors.initials: CM
authors.lastname: Waugh
authors.forename: Thijs J
authors.initials: TJ
authors.lastname: Hagenbeek
authors.forename: Hergen
authors.initials: H
authors.lastname: Spits
authors.forename: Doreen A
authors.initials: DA
authors.lastname: Cantrell
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D017353:Gene Deletion; D019426:Integrases / Q000378:metabolism; D008221:Lymphoid Tissue / Q000166:cytology; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000201:enzymology; D013601:T-Lymphocytes / Q000166:cytology* / Q000201:enzymology*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D015815:Cell Adhesion Molecules; D051858:Forkhead Transcription Factors; D019707:Receptors, Chemokine; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578564:Pdpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; C045073:Cre recombinase; D019426:Integrases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D020742:rhoA GTP-Binding Protein