IκB kinase-induced interaction of TPL-2 kinase with 14-3-3 is essential for Toll-like receptor activation of ERK-1 and -2 MAP kinases

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IκB kinase-induced interaction of TPL-2 kinase with 14-3-3 is essential for Toll-like receptor activation of ERK-1 and -2 MAP kinases. / Ben-Addi, Abduelhakem; Mambole-Dema, Agnes; Brender, Christine; Martin, Stephen R; Janzen, Julia; Kjaer, Sven; Smerdon, Stephen J; Ley, Steven C.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 23, 10.06.2014, p. E2394-403.

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Ben-Addi, Abduelhakem ; Mambole-Dema, Agnes ; Brender, Christine ; Martin, Stephen R ; Janzen, Julia ; Kjaer, Sven ; Smerdon, Stephen J ; Ley, Steven C. / IκB kinase-induced interaction of TPL-2 kinase with 14-3-3 is essential for Toll-like receptor activation of ERK-1 and -2 MAP kinases. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 23. pp. E2394-403.

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@article{b0728fe06c3a487f8ab5acc2ae371fb0,
title = "IκB kinase-induced interaction of TPL-2 kinase with 14-3-3 is essential for Toll-like receptor activation of ERK-1 and -2 MAP kinases",
abstract = "The MEK-1/2 kinase TPL-2 is critical for Toll-like receptor activation of the ERK-1/2 MAP kinase pathway during inflammatory responses, but it can transform cells following C-terminal truncation. IκB kinase (IKK) complex phosphorylation of the TPL-2 C terminus regulates full-length TPL-2 activation of ERK-1/2 by a mechanism that has remained obscure. Here, we show that TPL-2 Ser-400 phosphorylation by IKK and TPL-2 Ser-443 autophosphorylation cooperated to trigger TPL-2 association with 14-3-3. Recruitment of 14-3-3 to the phosphorylated C terminus stimulated TPL-2 MEK-1 kinase activity, which was essential for TPL-2 activation of ERK-1/2. The binding of 14-3-3 to TPL-2 was also indispensible for lipopolysaccharide-induced production of tumor necrosis factor by macrophages, which is regulated by TPL-2 independently of ERK-1/2 activation. Our data identify a key step in the activation of TPL-2 signaling and provide a mechanistic insight into how C-terminal deletion triggers the oncogenic potential of TPL-2 by rendering its kinase activity independent of 14-3-3 binding. ",
keywords = "14-3-3 Proteins/genetics, Animals, Cells, Cultured, Enzyme Activation, HEK293 Cells, Humans, I-kappa B Kinase/metabolism, Immunoblotting, Lipopolysaccharides/pharmacology, MAP Kinase Kinase Kinases/genetics, MAP Kinase Signaling System, Macrophages/drug effects, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitogen-Activated Protein Kinase 1/metabolism, Mitogen-Activated Protein Kinase 3/metabolism, NF-kappa B p50 Subunit/genetics, Phosphorylation, Protein Binding, Proto-Oncogene Proteins/genetics, Serine/genetics, Toll-Like Receptors/metabolism, Tumor Necrosis Factor-alpha/metabolism",
author = "Abduelhakem Ben-Addi and Agnes Mambole-Dema and Christine Brender and Martin, {Stephen R} and Julia Janzen and Sven Kjaer and Smerdon, {Stephen J} and Ley, {Steven C}",
year = "2014",
month = jun
day = "10",
doi = "10.1073/pnas.1320440111",
language = "English",
volume = "111",
pages = "E2394--403",
journal = "National Academy of Sciences. Proceedings",
issn = "1091-6490",
publisher = "National Academy of Sciences",
number = "23",

}

RIS

TY - JOUR

T1 - IκB kinase-induced interaction of TPL-2 kinase with 14-3-3 is essential for Toll-like receptor activation of ERK-1 and -2 MAP kinases

AU - Ben-Addi, Abduelhakem

AU - Mambole-Dema, Agnes

AU - Brender, Christine

AU - Martin, Stephen R

AU - Janzen, Julia

AU - Kjaer, Sven

AU - Smerdon, Stephen J

AU - Ley, Steven C

PY - 2014/6/10

Y1 - 2014/6/10

N2 - The MEK-1/2 kinase TPL-2 is critical for Toll-like receptor activation of the ERK-1/2 MAP kinase pathway during inflammatory responses, but it can transform cells following C-terminal truncation. IκB kinase (IKK) complex phosphorylation of the TPL-2 C terminus regulates full-length TPL-2 activation of ERK-1/2 by a mechanism that has remained obscure. Here, we show that TPL-2 Ser-400 phosphorylation by IKK and TPL-2 Ser-443 autophosphorylation cooperated to trigger TPL-2 association with 14-3-3. Recruitment of 14-3-3 to the phosphorylated C terminus stimulated TPL-2 MEK-1 kinase activity, which was essential for TPL-2 activation of ERK-1/2. The binding of 14-3-3 to TPL-2 was also indispensible for lipopolysaccharide-induced production of tumor necrosis factor by macrophages, which is regulated by TPL-2 independently of ERK-1/2 activation. Our data identify a key step in the activation of TPL-2 signaling and provide a mechanistic insight into how C-terminal deletion triggers the oncogenic potential of TPL-2 by rendering its kinase activity independent of 14-3-3 binding.

AB - The MEK-1/2 kinase TPL-2 is critical for Toll-like receptor activation of the ERK-1/2 MAP kinase pathway during inflammatory responses, but it can transform cells following C-terminal truncation. IκB kinase (IKK) complex phosphorylation of the TPL-2 C terminus regulates full-length TPL-2 activation of ERK-1/2 by a mechanism that has remained obscure. Here, we show that TPL-2 Ser-400 phosphorylation by IKK and TPL-2 Ser-443 autophosphorylation cooperated to trigger TPL-2 association with 14-3-3. Recruitment of 14-3-3 to the phosphorylated C terminus stimulated TPL-2 MEK-1 kinase activity, which was essential for TPL-2 activation of ERK-1/2. The binding of 14-3-3 to TPL-2 was also indispensible for lipopolysaccharide-induced production of tumor necrosis factor by macrophages, which is regulated by TPL-2 independently of ERK-1/2 activation. Our data identify a key step in the activation of TPL-2 signaling and provide a mechanistic insight into how C-terminal deletion triggers the oncogenic potential of TPL-2 by rendering its kinase activity independent of 14-3-3 binding.

KW - 14-3-3 Proteins/genetics

KW - Animals

KW - Cells, Cultured

KW - Enzyme Activation

KW - HEK293 Cells

KW - Humans

KW - I-kappa B Kinase/metabolism

KW - Immunoblotting

KW - Lipopolysaccharides/pharmacology

KW - MAP Kinase Kinase Kinases/genetics

KW - MAP Kinase Signaling System

KW - Macrophages/drug effects

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Mitogen-Activated Protein Kinase 1/metabolism

KW - Mitogen-Activated Protein Kinase 3/metabolism

KW - NF-kappa B p50 Subunit/genetics

KW - Phosphorylation

KW - Protein Binding

KW - Proto-Oncogene Proteins/genetics

KW - Serine/genetics

KW - Toll-Like Receptors/metabolism

KW - Tumor Necrosis Factor-alpha/metabolism

U2 - 10.1073/pnas.1320440111

DO - 10.1073/pnas.1320440111

M3 - Article

C2 - 24912162

VL - 111

SP - E2394-403

JO - National Academy of Sciences. Proceedings

JF - National Academy of Sciences. Proceedings

SN - 1091-6490

IS - 23

ER -