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.
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.
Waugh
Caryll
C
Department of Cell Biology and Immunology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom.
Sinclair
Linda
L
Finlay
David
D
Bayascas
Jose R
JR
Cantrell
Doreen
D
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D003602:Cytotoxicity, Immunologic; D004789:Enzyme Activation; D051858:Forkhead Transcription Factors / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008954:Models, Biological; D010716:Phosphatidylinositols / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology* / Q000201:enzymology*
D051858:Forkhead Transcription Factors; D010716:Phosphatidylinositols; D016201:Receptors, Lymphocyte Homing; C118303:phosphoinositide-3,4,5-triphosphate; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578564:Pdpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt
J Exp Med. 2006 Jul 10;203(7):1733-44
16785309
Nat Immunol. 2008 May;9(5):513-21
18391955
J Immunol. 2007 May 1;178(9):5443-53
17442925
PLoS Biol. 2007 Apr;5(4):e95
17407381
FEBS Lett. 2000 Nov 10;484(3):217-23
11078882
Nature. 2006 Jul 20;442(7100):299-302
16855590
J Biol Chem. 2000 Jul 7;275(27):20806-13
10764742
EMBO J. 2007 Jul 25;26(14):3441-50
17599070
Science. 2002 Aug 9;297(5583):1031-4
12130661
Immunity. 1994 Jul;1(4):247-60
7534203
Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):12105-10
17609365
J Exp Med. 2001 Oct 1;194(7):953-66
11581317
Nature. 2000 Mar 23;404(6776):402-7
10746729
Mol Cell Biol. 2008 May;28(10):3258-72
18347057
Nat Rev Immunol. 2004 May;4(5):325-35
15122198
Blood. 2006 Jul 15;108(2):600-8
16569767
Biochem J. 2003 Nov 1;375(Pt 3):531-8
12964941
Science. 2005 Apr 1;308(5718):114-8
15802604
J Immunol. 2007 Jun 15;178(12):7632-9
17548599
EMBO J. 2004 Oct 13;23(20):3918-28
15457207
Immunity. 2009 Mar 20;30(3):358-71
19285438
Nature. 2009 Mar 12;458(7235):211-4
19182777
J Virol. 2005 Apr;79(7):4510-3
15767451
Nat Immunol. 2007 Jul;8(7):743-52
17529983
Nature. 1989 Nov 30;342(6249):559-61
2573841
J Immunol. 2003 Mar 1;170(5):2647-54
12594293
J Immunol. 2005 Sep 1;175(5):2783-7
16116162
FEBS Lett. 2006 Oct 30;580(25):5845-50
17027005
Immunity. 2008 Jan;28(1):122-33
18164221
Nat Immunol. 2001 Aug;2(8):698-704
11477405
Nat Immunol. 2007 Dec;8(12):1295-301
18026082
Nat Immunol. 2009 Feb;10(2):176-84
19136962
Nat Immunol. 2004 May;5(5):539-45
15077109
EMBO J. 2003 Aug 15;22(16):4202-11
12912918
Nat Immunol. 2009 Feb;10(2):158-66
19122654
Biochem J. 1999 Feb 1;337 ( Pt 3):575-83
9895304
Trends Immunol. 2008 Apr;29(4):179-85
18328786
Cell. 1994 Jan 28;76(2):301-14
7507411
Blood. 2008 Feb 1;111(3):1464-71
18006698
Nat Immunol. 2002 Nov;3(11):1090-6
12389041
J Exp Med. 2003 Nov 3;198(9):1323-35
14597735
Nat Immunol. 2002 Jun;3(6):515-21
12032565
J Immunol. 2008 Sep 1;181(5):2980-9
18713968
J Immunol. 2005 Apr 1;174(7):4161-71
15778376
Immunol Rev. 2006 Jun;211:93-103
16824120
Biochem J. 2005 Jan 15;385(Pt 2):399-408
15456405
Curr Biol. 1997 Apr 1;7(4):261-9
9094314
PLoS One. 2007 Oct 03;2(10):e992
17912369
Nat Immunol. 2002 Nov;3(11):1082-9
12389042
J Immunol. 1997 Aug 15;159(4):1686-94
9257829
Nat Immunol. 2008 Mar;9(3):292-300
18246069