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A RING to rule them all? Insights into the Map3k1 PHD motif provide a new mechanistic understanding into the diverse roles of Map3k1.

Suddason T, Gallagher E - Cell Death Differ. (2015)

Bottom Line: Despite the sizable number of components that comprise Mapk cascades, Map3k1 is the only element that contains both a kinase domain and a plant homeodomain (PHD) motif, allowing Map3k1 to regulate the protein phosphorylation and ubiquitin proteasome systems.As such, Map3k1 has complex roles in the regulation of cell death, survival, migration and differentiation.Recent gene knockin of Map3k1 to mutate the E2 binding site within the Map3k1 PHD motif and high throughput ubiquitin protein array screening for Map3k1 PHD motif substrates provide critical novel insights into Map3k1 PHD motif signal transduction and bring a brand-new understanding to Map3k1 signaling in mammalian biology.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Imperial College London, Du Cane Road, London, UK.

ABSTRACT
Despite the sizable number of components that comprise Mapk cascades, Map3k1 is the only element that contains both a kinase domain and a plant homeodomain (PHD) motif, allowing Map3k1 to regulate the protein phosphorylation and ubiquitin proteasome systems. As such, Map3k1 has complex roles in the regulation of cell death, survival, migration and differentiation. Numerous mouse and human genetic analyses have demonstrated that Map3k1 is of critical importance for the immune system, cardiac tissue, testis, wound healing, tumorigenesis and cancer. Recent gene knockin of Map3k1 to mutate the E2 binding site within the Map3k1 PHD motif and high throughput ubiquitin protein array screening for Map3k1 PHD motif substrates provide critical novel insights into Map3k1 PHD motif signal transduction and bring a brand-new understanding to Map3k1 signaling in mammalian biology.

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Related in: MedlinePlus

The Map3k1 PHD motif regulates Tabs in response to cytokine stimulation. Following Tgf-β treatment, the Map3k1 PHD motif binds and transfers Lys63-linked poly-Ub onto Tab1 to enhance Map3k7 activation. Tab2, although not a Map3k1 PHD motif substrate, can be recruited to the Map3k1:Map3k7 Ub signaling complex by the Ub binding ZnF motif of Tab2.
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fig2: The Map3k1 PHD motif regulates Tabs in response to cytokine stimulation. Following Tgf-β treatment, the Map3k1 PHD motif binds and transfers Lys63-linked poly-Ub onto Tab1 to enhance Map3k7 activation. Tab2, although not a Map3k1 PHD motif substrate, can be recruited to the Map3k1:Map3k7 Ub signaling complex by the Ub binding ZnF motif of Tab2.

Mentions: Ubiquitination assays by orthogonal approaches confirmed that the Map3k1 PHD can transfer Lys63-linked poly-Ub onto recombinant Tab1, and also other scaffold proteins, namely Traf2, TNFAIP3 interacting protein (Tnip) 1 (Tnip1), Tnip2 and Signal transducing adapter molecule 1 (Stam1).72 Of these Map3k1 PHD motif substrates, and after immunoprecipitation from the WT and Map3k1mPHD ES cells stimulated by Tgf-β, only Tab1 was found to be significantly ubiquitinated by Lys63-linked poly-Ub in WT and not Map3k1mPHD ES cells.72 Generation of Tab1−/− ES cells revealed that they, like Map3k1mPHD ES cells, are deficient in Egf- and Tgf-β-induced Mapk and Map3k7 (also known as Tak1) activation.72 Mapping of the Tab1 ubiquitination sites mediated by the Map3k1 PHD and Ube2N:Ube2V1 identified Lys294, Lys319, Lys335 and Lys350 as being important for Tab1 ubiquitination by the PHD motif. Map3k1 can interact with and transfer Lys63-linked poly-Ub onto Tab1 by its PHD motif to potentiate the protein–protein interaction between Tab1 and Map3k7.72 Tab2, though not itself a Map3k1 PHD substrate, can be recruited into the Tab1:Map3k1 Ub complex to form a ternary complex that is dependent upon the Tab2 zinc finger (ZnF), a motif that can interact with proteins that possess Lys63-linked poly-Ub chains.72, 77 Recruitment of Tab2 into the Map3k1:Tab1 signaling complex may facilitate a further downstream signaling from Tgf-β receptors (Tgfβrs) and Egf receptors (Egfrs) (Figure 2). The formation of a Ub signaling complex between Tab1:Map3k1:Map3k7 offers a plausible explanation for why Map3k1mPHD ES cells or WT ES cells treated with the Map3k7 chemical inhibitor (5Z)-7-oxozeaenol both lose Mapk activation following stimulation by Tgf-β or Egf cytokines.72 Chemical inhibition using the Ube2N inhibitor NSC697923 demonstrates that Ube2N is also critical for Map3k7 and Mapk activation in ES cells following treatment with Tgf-β or Egf, and Ube2N is also important for Tgf-β-induced Mapk activation in breast cancer cells.72, 78 However, unlike CD40 signaling in B cells, where Traf2 is critical for Mapk8/9 and Mapk14 activation,52, 53 instead for Tgfβrs Traf6 is critical for Mapk activation.79 The identification of a new PHD motif substrate that forms the lynchpin between Tgf-β-dependent Mapk pathway activation and stem cell differentiation further complicates the role for the Map3k1 PHD motif in apoptosis, and suggests that under conditions of cell death induced by hyperosmotic stress Map3k1 may silence Mapk signaling, while when stimulated by cytokines the Map3k1 PHD plays a role in promoting cell survival and differentiation by activating Mapks (Figure 3).


A RING to rule them all? Insights into the Map3k1 PHD motif provide a new mechanistic understanding into the diverse roles of Map3k1.

Suddason T, Gallagher E - Cell Death Differ. (2015)

The Map3k1 PHD motif regulates Tabs in response to cytokine stimulation. Following Tgf-β treatment, the Map3k1 PHD motif binds and transfers Lys63-linked poly-Ub onto Tab1 to enhance Map3k7 activation. Tab2, although not a Map3k1 PHD motif substrate, can be recruited to the Map3k1:Map3k7 Ub signaling complex by the Ub binding ZnF motif of Tab2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4356348&req=5

fig2: The Map3k1 PHD motif regulates Tabs in response to cytokine stimulation. Following Tgf-β treatment, the Map3k1 PHD motif binds and transfers Lys63-linked poly-Ub onto Tab1 to enhance Map3k7 activation. Tab2, although not a Map3k1 PHD motif substrate, can be recruited to the Map3k1:Map3k7 Ub signaling complex by the Ub binding ZnF motif of Tab2.
Mentions: Ubiquitination assays by orthogonal approaches confirmed that the Map3k1 PHD can transfer Lys63-linked poly-Ub onto recombinant Tab1, and also other scaffold proteins, namely Traf2, TNFAIP3 interacting protein (Tnip) 1 (Tnip1), Tnip2 and Signal transducing adapter molecule 1 (Stam1).72 Of these Map3k1 PHD motif substrates, and after immunoprecipitation from the WT and Map3k1mPHD ES cells stimulated by Tgf-β, only Tab1 was found to be significantly ubiquitinated by Lys63-linked poly-Ub in WT and not Map3k1mPHD ES cells.72 Generation of Tab1−/− ES cells revealed that they, like Map3k1mPHD ES cells, are deficient in Egf- and Tgf-β-induced Mapk and Map3k7 (also known as Tak1) activation.72 Mapping of the Tab1 ubiquitination sites mediated by the Map3k1 PHD and Ube2N:Ube2V1 identified Lys294, Lys319, Lys335 and Lys350 as being important for Tab1 ubiquitination by the PHD motif. Map3k1 can interact with and transfer Lys63-linked poly-Ub onto Tab1 by its PHD motif to potentiate the protein–protein interaction between Tab1 and Map3k7.72 Tab2, though not itself a Map3k1 PHD substrate, can be recruited into the Tab1:Map3k1 Ub complex to form a ternary complex that is dependent upon the Tab2 zinc finger (ZnF), a motif that can interact with proteins that possess Lys63-linked poly-Ub chains.72, 77 Recruitment of Tab2 into the Map3k1:Tab1 signaling complex may facilitate a further downstream signaling from Tgf-β receptors (Tgfβrs) and Egf receptors (Egfrs) (Figure 2). The formation of a Ub signaling complex between Tab1:Map3k1:Map3k7 offers a plausible explanation for why Map3k1mPHD ES cells or WT ES cells treated with the Map3k7 chemical inhibitor (5Z)-7-oxozeaenol both lose Mapk activation following stimulation by Tgf-β or Egf cytokines.72 Chemical inhibition using the Ube2N inhibitor NSC697923 demonstrates that Ube2N is also critical for Map3k7 and Mapk activation in ES cells following treatment with Tgf-β or Egf, and Ube2N is also important for Tgf-β-induced Mapk activation in breast cancer cells.72, 78 However, unlike CD40 signaling in B cells, where Traf2 is critical for Mapk8/9 and Mapk14 activation,52, 53 instead for Tgfβrs Traf6 is critical for Mapk activation.79 The identification of a new PHD motif substrate that forms the lynchpin between Tgf-β-dependent Mapk pathway activation and stem cell differentiation further complicates the role for the Map3k1 PHD motif in apoptosis, and suggests that under conditions of cell death induced by hyperosmotic stress Map3k1 may silence Mapk signaling, while when stimulated by cytokines the Map3k1 PHD plays a role in promoting cell survival and differentiation by activating Mapks (Figure 3).

Bottom Line: Despite the sizable number of components that comprise Mapk cascades, Map3k1 is the only element that contains both a kinase domain and a plant homeodomain (PHD) motif, allowing Map3k1 to regulate the protein phosphorylation and ubiquitin proteasome systems.As such, Map3k1 has complex roles in the regulation of cell death, survival, migration and differentiation.Recent gene knockin of Map3k1 to mutate the E2 binding site within the Map3k1 PHD motif and high throughput ubiquitin protein array screening for Map3k1 PHD motif substrates provide critical novel insights into Map3k1 PHD motif signal transduction and bring a brand-new understanding to Map3k1 signaling in mammalian biology.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Imperial College London, Du Cane Road, London, UK.

ABSTRACT
Despite the sizable number of components that comprise Mapk cascades, Map3k1 is the only element that contains both a kinase domain and a plant homeodomain (PHD) motif, allowing Map3k1 to regulate the protein phosphorylation and ubiquitin proteasome systems. As such, Map3k1 has complex roles in the regulation of cell death, survival, migration and differentiation. Numerous mouse and human genetic analyses have demonstrated that Map3k1 is of critical importance for the immune system, cardiac tissue, testis, wound healing, tumorigenesis and cancer. Recent gene knockin of Map3k1 to mutate the E2 binding site within the Map3k1 PHD motif and high throughput ubiquitin protein array screening for Map3k1 PHD motif substrates provide critical novel insights into Map3k1 PHD motif signal transduction and bring a brand-new understanding to Map3k1 signaling in mammalian biology.

Show MeSH
Related in: MedlinePlus