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CUL3 and protein kinases: insights from PLK1/KLHL22 interaction.

Metzger T, Kleiss C, Sumara I - Cell Cycle (2013)

Bottom Line: We find that kinase activity of PLK1 is redundant for its targeting for CUL3-ubiquitination.Moreover, CUL3/KLHL22 may contact 2 distinct motifs within PLK1 protein, consistent with the bivalent mode of substrate targeting found in other CUL3-based complexes.We discuss these findings in the context of the existing knowledge on other protein kinases and substrates targeted by CUL3-based E3-ligases.

View Article: PubMed Central - PubMed

Affiliation: Institute of Genetics and Molecular and Cellular Biology, Illkirch, France.

ABSTRACT
Posttranslational mechanisms drive fidelity of cellular processes. Phosphorylation and ubiquitination of substrates represent very common, covalent, posttranslational modifications and are often co-regulated. Phosphorylation may play a critical role both by directly regulating E3-ubiquitin ligases and/or by ensuring specificity of the ubiquitination substrate. Importantly, many kinases are not only critical regulatory components of these pathways but also represent themselves the direct ubiquitination substrates. Recent data suggest the role of CUL3-based ligases in both proteolytic and non-proteolytic regulation of protein kinases. Our own recent study identified the mitotic kinase PLK1 as a direct target of the CUL3 E3-ligase complex containing BTB-KELCH adaptor protein KLHL22. (1) In this study, we aim at gaining mechanistic insights into CUL3-mediated regulation of the substrates, in particular protein kinases, by analyzing mechanisms of interaction between KLHL22 and PLK1. We find that kinase activity of PLK1 is redundant for its targeting for CUL3-ubiquitination. Moreover, CUL3/KLHL22 may contact 2 distinct motifs within PLK1 protein, consistent with the bivalent mode of substrate targeting found in other CUL3-based complexes. We discuss these findings in the context of the existing knowledge on other protein kinases and substrates targeted by CUL3-based E3-ligases.

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Figure 1. Two common models of substrates recognition by E3-ligase complexes. SCF ligases interact with the phosphorylated residues on the substrates, which create a so-called “phosphodegron”. The APC/C complex recognizes specific short motifs within the amino acid sequence of the targeted proteins, and its activity is regulated by phosphorylation. Little is known about mechanisms of substrate targeting by CUL3-based E3-ligases.
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Figure 1: Figure 1. Two common models of substrates recognition by E3-ligase complexes. SCF ligases interact with the phosphorylated residues on the substrates, which create a so-called “phosphodegron”. The APC/C complex recognizes specific short motifs within the amino acid sequence of the targeted proteins, and its activity is regulated by phosphorylation. Little is known about mechanisms of substrate targeting by CUL3-based E3-ligases.

Mentions: Interestingly, phosphorylation and ubiquitination pathways are often interconnected. Phosphorylation may play a critical role both by directly regulating E3-ligases and/or by ensuring substrate specificity. For example, the APC/C subunits and the substrate adaptors are differentially phosphorylated during mitosis and mitotic exit, regulating activity of these enzymes.8,9 On the other hand, the substrates of the SCF E3-ligases need to be phosphorylated, creating a so-called “phosphodegron”, in order to be efficiently targeted for ubiquitination10 (Fig. 1). Importantly, many kinases are not only critical regulatory components of these pathways but also represent themselves the direct ubiquitination substrates. In many cases, ubiquitination of the kinases may lead to their subsequent proteasomal degradation, ultimately attenuating their enzymatic activity, as has been demonstrated for some mitotic kinases targeted by the APC/C E3-ligase.11 However, ubiquitination may also serve non-proteolytic functions, leading to regulation of subcellular localization, binding affinities, or even enzymatic activities.12 Recent data suggest the role of CUL3-based ligases in both proteolytic and non-proteolytic regulation of protein kinases (Table 1 and references therein). Our own recent study identified the mitotic kinase PLK1 as a direct target of the CUL3 E3-ligase complex containing BTB-KELCH adaptor protein KLHL22.1 CUL3/KLHL22-mediated ubiquitination serves a non-proteolytic function and regulates the subcellular localization of PLK1 specifically at the kinetochores. Dissociation of the ubiquitinated PLK1 from kinetochores and thereby reduction of its localized kinase activity is an essential event for the anaphase onset in human cells.1


CUL3 and protein kinases: insights from PLK1/KLHL22 interaction.

Metzger T, Kleiss C, Sumara I - Cell Cycle (2013)

Figure 1. Two common models of substrates recognition by E3-ligase complexes. SCF ligases interact with the phosphorylated residues on the substrates, which create a so-called “phosphodegron”. The APC/C complex recognizes specific short motifs within the amino acid sequence of the targeted proteins, and its activity is regulated by phosphorylation. Little is known about mechanisms of substrate targeting by CUL3-based E3-ligases.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3755079&req=5

Figure 1: Figure 1. Two common models of substrates recognition by E3-ligase complexes. SCF ligases interact with the phosphorylated residues on the substrates, which create a so-called “phosphodegron”. The APC/C complex recognizes specific short motifs within the amino acid sequence of the targeted proteins, and its activity is regulated by phosphorylation. Little is known about mechanisms of substrate targeting by CUL3-based E3-ligases.
Mentions: Interestingly, phosphorylation and ubiquitination pathways are often interconnected. Phosphorylation may play a critical role both by directly regulating E3-ligases and/or by ensuring substrate specificity. For example, the APC/C subunits and the substrate adaptors are differentially phosphorylated during mitosis and mitotic exit, regulating activity of these enzymes.8,9 On the other hand, the substrates of the SCF E3-ligases need to be phosphorylated, creating a so-called “phosphodegron”, in order to be efficiently targeted for ubiquitination10 (Fig. 1). Importantly, many kinases are not only critical regulatory components of these pathways but also represent themselves the direct ubiquitination substrates. In many cases, ubiquitination of the kinases may lead to their subsequent proteasomal degradation, ultimately attenuating their enzymatic activity, as has been demonstrated for some mitotic kinases targeted by the APC/C E3-ligase.11 However, ubiquitination may also serve non-proteolytic functions, leading to regulation of subcellular localization, binding affinities, or even enzymatic activities.12 Recent data suggest the role of CUL3-based ligases in both proteolytic and non-proteolytic regulation of protein kinases (Table 1 and references therein). Our own recent study identified the mitotic kinase PLK1 as a direct target of the CUL3 E3-ligase complex containing BTB-KELCH adaptor protein KLHL22.1 CUL3/KLHL22-mediated ubiquitination serves a non-proteolytic function and regulates the subcellular localization of PLK1 specifically at the kinetochores. Dissociation of the ubiquitinated PLK1 from kinetochores and thereby reduction of its localized kinase activity is an essential event for the anaphase onset in human cells.1

Bottom Line: We find that kinase activity of PLK1 is redundant for its targeting for CUL3-ubiquitination.Moreover, CUL3/KLHL22 may contact 2 distinct motifs within PLK1 protein, consistent with the bivalent mode of substrate targeting found in other CUL3-based complexes.We discuss these findings in the context of the existing knowledge on other protein kinases and substrates targeted by CUL3-based E3-ligases.

View Article: PubMed Central - PubMed

Affiliation: Institute of Genetics and Molecular and Cellular Biology, Illkirch, France.

ABSTRACT
Posttranslational mechanisms drive fidelity of cellular processes. Phosphorylation and ubiquitination of substrates represent very common, covalent, posttranslational modifications and are often co-regulated. Phosphorylation may play a critical role both by directly regulating E3-ubiquitin ligases and/or by ensuring specificity of the ubiquitination substrate. Importantly, many kinases are not only critical regulatory components of these pathways but also represent themselves the direct ubiquitination substrates. Recent data suggest the role of CUL3-based ligases in both proteolytic and non-proteolytic regulation of protein kinases. Our own recent study identified the mitotic kinase PLK1 as a direct target of the CUL3 E3-ligase complex containing BTB-KELCH adaptor protein KLHL22. (1) In this study, we aim at gaining mechanistic insights into CUL3-mediated regulation of the substrates, in particular protein kinases, by analyzing mechanisms of interaction between KLHL22 and PLK1. We find that kinase activity of PLK1 is redundant for its targeting for CUL3-ubiquitination. Moreover, CUL3/KLHL22 may contact 2 distinct motifs within PLK1 protein, consistent with the bivalent mode of substrate targeting found in other CUL3-based complexes. We discuss these findings in the context of the existing knowledge on other protein kinases and substrates targeted by CUL3-based E3-ligases.

Show MeSH