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Phosphoinositide (3,4,5)-triphosphate binding to phosphoinositide-dependent kinase 1 regulates a protein kinase B/Akt signaling threshold that dictates T-cell migration, not proliferation.
- Source :
-
Molecular and cellular biology [Mol Cell Biol] 2009 Nov; Vol. 29 (21), pp. 5952-62. Date of Electronic Publication: 2009 Aug 24. - Publication Year :
- 2009
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Abstract
- The present study explored the consequences of phosphoinositide (3,4,5)-triphosphate [PI(3,4,5)P(3)] binding to the pleckstrin homology (PH) domain of the serine/threonine kinase 3-phosphoinositide-dependent kinase 1 (PDK1). The salient finding is that PDK1 directly transduces the PI(3,4,5)P(3) signaling that determines T-cell trafficking programs but not T-cell growth and proliferation. The integrity of the PDK1 PH domain thus is not required for PDK1 catalytic activity or to support cell survival and the proliferation of thymic and peripheral T cells. However, a PDK1 mutant that cannot bind PI(3,4,5)P(3) cannot trigger the signals that terminate the expression of the transcription factor KLF2 in activated T cells and cannot switch the chemokine and adhesion receptor profile of naive T cells to the profile of effector T cells. The PDK1 PH domain also is required for the maximal activation of Akt/protein kinase B (PKB) and for the maximal phosphorylation and inactivation of Foxo family transcription factors in T cells. PI(3,4,5)P(3) binding to PDK1 and the strength of PKB activity thus can dictate the nature of the T-cell response. Low levels of PKB activity can be sufficient for T-cell proliferation but insufficient to initiate the migratory program of effector T cells.
- Subjects :
- 3-Phosphoinositide-Dependent Protein Kinases
Animals
Cell Differentiation
Cell Proliferation
Cell Survival
Cytotoxicity, Immunologic
Enzyme Activation
Forkhead Transcription Factors metabolism
Lymphocyte Activation
Mice
Models, Biological
Phosphorylation
Receptors, Lymphocyte Homing metabolism
Cell Movement
Phosphatidylinositols metabolism
Protein Serine-Threonine Kinases metabolism
Proto-Oncogene Proteins c-akt metabolism
Signal Transduction
T-Lymphocytes cytology
T-Lymphocytes enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 1098-5549
- Volume :
- 29
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- Molecular and cellular biology
- Publication Type :
- Academic Journal
- Accession number :
- 19703999
- Full Text :
- https://doi.org/10.1128/MCB.00585-09