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

Abduelhakem Ben-Addi; Agnes Mambole-Dema; Christine Brender; Stephen R Martin; Julia Janzen; Sven Kjaer; Stephen J Smerdon; Steven C Ley

doi:10.1073/pnas.1320440111

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

Abduelhakem Ben-Addi
, Agnes Mambole-Dema
, Christine Brender
, Stephen R Martin
, Julia Janzen
, Sven Kjaer
, Stephen J Smerdon
, Steven C Ley

Cancer and Genomic Sciences

Research output: Contribution to journal › Article › peer-review

25 Citations (Scopus)

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.

Original language	English
Pages (from-to)	E2394-E2403
Number of pages	10
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	111
Issue number	23
Early online date	27 May 2014
DOIs	https://doi.org/10.1073/pnas.1320440111
Publication status	Published - 10 Jun 2014

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
inflammation
NF-κB
MAP3K8

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Cite this

Ben-Addi, A., Mambole-Dema, A., Brender, C., Martin, S. R., Janzen, J., Kjaer, S., Smerdon, S. J., & Ley, S. C. (2014). 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. Proceedings of the National Academy of Sciences of the United States of America, 111(23), E2394-E2403. https://doi.org/10.1073/pnas.1320440111

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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. ",

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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--E2403",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

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Ben-Addi, A, Mambole-Dema, A, Brender, C, Martin, SR, Janzen, J, Kjaer, S, Smerdon, SJ & Ley, SC 2014, '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', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 23, pp. E2394-E2403. https://doi.org/10.1073/pnas.1320440111

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 et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 23, 10.06.2014, p. E2394-E2403.

Research output: Contribution to journal › Article › peer-review

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

KW - inflammation

KW - NF-κB

KW - MAP3K8

U2 - 10.1073/pnas.1320440111

DO - 10.1073/pnas.1320440111

M3 - Article

C2 - 24912162

SN - 1091-6490

VL - 111

SP - E2394-E2403

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 23

ER -

Ben-Addi A, Mambole-Dema A, Brender C, Martin SR, Janzen J, Kjaer S et al. 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. Proceedings of the National Academy of Sciences of the United States of America. 2014 Jun 10;111(23):E2394-E2403. Epub 2014 May 27. doi: 10.1073/pnas.1320440111

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

Keywords

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