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TRAF2-MLK3 interaction is essential for TNF-alpha-induced MLK3 activation.

Sondarva G, Kundu CN, Mehrotra S, Mishra R, Rangasamy V, Sathyanarayana P, Ray RS, Rana B, Rana A - Cell Res. (2009)

Bottom Line: TNF receptor-associated factors (TRAFs) are adapter molecules that are recruited to cytoplasmic end of TNF receptor and mediate the downstream signaling, including activation of JNK.Furthermore the downstream target of MLK3, JNK was activated by TNF-alpha in a TRAF2-dependent manner.Hence, our data show that the direct interaction between TRAF2 and MLK3 is required for TNF-alpha-induced activation of MLK3 and its downstream target, JNK.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA.

ABSTRACT
Mixed lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase that is activated by tumor necrosis factor-alpha (TNF-alpha) and specifically activates c-Jun N-terminal kinase (JNK) on TNF-alpha stimulation. The mechanism by which TNF-alpha activates MLK3 is still not known. TNF receptor-associated factors (TRAFs) are adapter molecules that are recruited to cytoplasmic end of TNF receptor and mediate the downstream signaling, including activation of JNK. Here, we report that MLK3 associates with TRAF2, TRAF5 and TRAF6; however only TRAF2 can significantly induce the kinase activity of MLK3. The interaction domain of TRAF2 maps to the TRAF domain and for MLK3 to its C-terminal half (amino acids 511-847). Endogenous TRAF2 and MLK3 associate with each other in response to TNF-alpha treatment in a time-dependent manner. The association between MLK3 and TRAF2 mediates MLK3 activation and competition with the TRAF2 deletion mutant that binds to MLK3 attenuates MLK3 kinase activity in a dose-dependent manner, on TNF-alpha treatment. Furthermore the downstream target of MLK3, JNK was activated by TNF-alpha in a TRAF2-dependent manner. Hence, our data show that the direct interaction between TRAF2 and MLK3 is required for TNF-alpha-induced activation of MLK3 and its downstream target, JNK.

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A model of MLK3 activation by TRAF2 via TNF-pathway. The pro-inflammatory cytokine TNF-α binds to its receptor, TNFR that allows death domain containing adaptor protein TRADD to associate with the death domain (DD) of TNFR at the cytoplasmic end. The TRAF2 binds with TRADD and MLK3. This protein-protein interaction allows MLK3 activation and its downstream target JNK via MKK4 and MKK7 (two MAPKK). The other details about NF-kB activation by TRAF2 is described in the text.
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Figure 7: A model of MLK3 activation by TRAF2 via TNF-pathway. The pro-inflammatory cytokine TNF-α binds to its receptor, TNFR that allows death domain containing adaptor protein TRADD to associate with the death domain (DD) of TNFR at the cytoplasmic end. The TRAF2 binds with TRADD and MLK3. This protein-protein interaction allows MLK3 activation and its downstream target JNK via MKK4 and MKK7 (two MAPKK). The other details about NF-kB activation by TRAF2 is described in the text.


TRAF2-MLK3 interaction is essential for TNF-alpha-induced MLK3 activation.

Sondarva G, Kundu CN, Mehrotra S, Mishra R, Rangasamy V, Sathyanarayana P, Ray RS, Rana B, Rana A - Cell Res. (2009)

A model of MLK3 activation by TRAF2 via TNF-pathway. The pro-inflammatory cytokine TNF-α binds to its receptor, TNFR that allows death domain containing adaptor protein TRADD to associate with the death domain (DD) of TNFR at the cytoplasmic end. The TRAF2 binds with TRADD and MLK3. This protein-protein interaction allows MLK3 activation and its downstream target JNK via MKK4 and MKK7 (two MAPKK). The other details about NF-kB activation by TRAF2 is described in the text.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2801772&req=5

Figure 7: A model of MLK3 activation by TRAF2 via TNF-pathway. The pro-inflammatory cytokine TNF-α binds to its receptor, TNFR that allows death domain containing adaptor protein TRADD to associate with the death domain (DD) of TNFR at the cytoplasmic end. The TRAF2 binds with TRADD and MLK3. This protein-protein interaction allows MLK3 activation and its downstream target JNK via MKK4 and MKK7 (two MAPKK). The other details about NF-kB activation by TRAF2 is described in the text.
Bottom Line: TNF receptor-associated factors (TRAFs) are adapter molecules that are recruited to cytoplasmic end of TNF receptor and mediate the downstream signaling, including activation of JNK.Furthermore the downstream target of MLK3, JNK was activated by TNF-alpha in a TRAF2-dependent manner.Hence, our data show that the direct interaction between TRAF2 and MLK3 is required for TNF-alpha-induced activation of MLK3 and its downstream target, JNK.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA.

ABSTRACT
Mixed lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase that is activated by tumor necrosis factor-alpha (TNF-alpha) and specifically activates c-Jun N-terminal kinase (JNK) on TNF-alpha stimulation. The mechanism by which TNF-alpha activates MLK3 is still not known. TNF receptor-associated factors (TRAFs) are adapter molecules that are recruited to cytoplasmic end of TNF receptor and mediate the downstream signaling, including activation of JNK. Here, we report that MLK3 associates with TRAF2, TRAF5 and TRAF6; however only TRAF2 can significantly induce the kinase activity of MLK3. The interaction domain of TRAF2 maps to the TRAF domain and for MLK3 to its C-terminal half (amino acids 511-847). Endogenous TRAF2 and MLK3 associate with each other in response to TNF-alpha treatment in a time-dependent manner. The association between MLK3 and TRAF2 mediates MLK3 activation and competition with the TRAF2 deletion mutant that binds to MLK3 attenuates MLK3 kinase activity in a dose-dependent manner, on TNF-alpha treatment. Furthermore the downstream target of MLK3, JNK was activated by TNF-alpha in a TRAF2-dependent manner. Hence, our data show that the direct interaction between TRAF2 and MLK3 is required for TNF-alpha-induced activation of MLK3 and its downstream target, JNK.

Show MeSH
Related in: MedlinePlus