Tpl2 (tumor progression locus 2) phosphorylation at Thr290 is induced by lipopolysaccharide via an Iκ-B kinase-β-dependent pathway and is required for Tpl2 activation by external signals

被引:44
作者
Cho, J
Melnick, M
Solidakis, GP
Tsichlis, PN
机构
[1] Tufts Univ, New England Med Ctr, Mol Oncol Res Inst, Boston, MA 02111 USA
[2] Tufts Canc Ctr, Boston, MA 02111 USA
[3] Cell Signaling Technol Inc, Beverly, MA 01915 USA
关键词
D O I
10.1074/jbc.M413554200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The serine-threonine protein kinase encoded by the tumor progression locus 2 ( Tpl2) proto-oncogene transduces Toll-like receptor and death receptor signals in a variety of cell types. Here we show that Tpl2 undergoes phosphorylation at Thr(290) both in cells overexpressing Tpl2 and in cells stimulated with lipopolysaccharide (LPS) or tumor necrosis factor-alpha and that phosphorylation on this site parallels Tpl2 activation. Reconstitution of Tpl2(-/-) macrophages with wild type Tpl2 or Tpl2 T290D restored ERK activation by LPS, whereas reconstitution of the same cells with Tpl2 T290A did not, suggesting that phosphorylation at Thr290 is required for the physiological activation of Tpl2 by external signals. Both the wild type Tpl2 and the kinase-inactive mutant Tpl2 K167M undergo Thr290 phosphorylation, suggesting that Thr290 may be a site of trans-phosphorylation rather than auto-phosphorylation. Pretreatment of 293 cells and primary macrophages with the I kappa-B kinase-beta (IKK beta) inhibitor PS-1145 blocked Tpl2 phosphorylation at Thr290, suggesting that phosphorylation depends on IKK beta, an obligatory positive regulator of Tpl2. We conclude that Tpl2 phosphorylation at Thr290 is induced by LPS, depends on IKK beta, and is required for the physiological activation of Tpl2 by external signals.
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页码:20442 / 20448
页数:7
相关论文
共 28 条
  • [1] Lipopolysaccharide activation of the TPL-2/MEK/extracellular signal-regulated kinase mitogen-activated protein kinase cascade is regulated by IκB kinase-induced proteolysis of NF-κB1 p105
    Beinke, S
    Robinson, MJ
    Hugunin, M
    Ley, SC
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 2004, 24 (21) : 9658 - 9667
  • [2] TPL-2 kinase regulates the proteolysis of the NF-κB-inhibitory protein NF-κB1 p105
    Belich, MP
    Salmerón, A
    Johnston, LH
    Ley, SC
    [J]. NATURE, 1999, 397 (6717) : 363 - 368
  • [3] BOYLE WJ, 1991, METHOD ENZYMOL, V201, P110
  • [4] Tpl-2 is an oncogenic kinase that is activated by carboxy-terminal truncation
    Ceci, JD
    Patriotis, CP
    Tsatsanis, C
    Makris, AM
    Kovatch, R
    Swing, DA
    Jenkins, NA
    Tsichlis, PN
    Copeland, NG
    [J]. GENES & DEVELOPMENT, 1997, 11 (06) : 688 - 700
  • [5] Multiple mitogen-activated protein kinase signaling pathways connect the Cot oncoprotein to the c-jun promoter and to cellular transformation
    Chiariello, M
    Marinissen, MJ
    Gutkind, JS
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 2000, 20 (05) : 1747 - 1758
  • [6] Phosphorylation at Thr-290 regulates Tpl2 binding to NF-κB1/p105 and Tpl2 activation and degradation by lipopolysaccharide
    Cho, JH
    Tsichlis, PN
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (07) : 2350 - 2355
  • [7] TNF-α induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway
    Dumitru, CD
    Ceci, JD
    Tsatsanis, C
    Kontoyiannis, D
    Stamatakis, K
    Lin, JH
    Patriotis, C
    Jenkins, NA
    Copeland, NG
    Kollias, G
    Tsichlis, PN
    [J]. CELL, 2000, 103 (07) : 1071 - 1083
  • [8] Tpl2 transduces CD40 and TNF signals that activate ERK and regulates IgE induction by CD40
    Eliopoulos, AG
    Wang, CC
    Dumitru, CD
    Tsichlis, PN
    [J]. EMBO JOURNAL, 2003, 22 (15) : 3855 - 3864
  • [9] Induction of COX-2 by LPS in macrophages is regulated by Tpl2-dependent CREB activation signals
    Eliopoulos, AG
    Dumitru, CD
    Wang, CC
    Cho, JH
    Tsichlis, PN
    [J]. EMBO JOURNAL, 2002, 21 (18) : 4831 - 4840
  • [10] Erny KM, 1996, ONCOGENE, V13, P2015