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LEM-4 promotes rapid dephosphorylation of BAF during mitotic exit.

Gorjánácz M - Nucleus (2012)

Bottom Line: We have identified LEM‑4, a conserved protein of the nuclear envelope, as an essential coordinator of kinase and phosphatase activities during mitotic exit.Inhibition of VRK‑1 kinase and promotion of a PP2A phosphatase complex by LEM‑4 tightly regulate the phosphorylation state of BAF, an essential player of nuclear reformation at the end of mitosis.Here I offer extended comments on the contribution of LEM‑4 in the regulation of protein phosphorylation and nuclear reformation.

View Article: PubMed Central - PubMed

Affiliation: European Molecular Biology Laboratory; Heidelberg, Germany. gorjanac@embl.de

ABSTRACT
The transitions between the successive cell cycle stages depend on reversible protein phosphorylation events. The phosphorylation state of every protein within a cell is strictly determined by spatiotemporally controlled kinase and phosphatase activities. Nuclear disassembly and reassembly during open mitosis in higher eukaryotic cells is one such process that is tightly regulated by the reversible phosphorylation of key proteins. However, little is known about the regulation of these mitotic events. In particular, although kinase function during entry into mitosis is better studied, very little is known about how proteins are dephosphorylated to allow nuclear reformation at the end of mitosis. We have identified LEM‑4, a conserved protein of the nuclear envelope, as an essential coordinator of kinase and phosphatase activities during mitotic exit. Inhibition of VRK‑1 kinase and promotion of a PP2A phosphatase complex by LEM‑4 tightly regulate the phosphorylation state of BAF, an essential player of nuclear reformation at the end of mitosis. Here I offer extended comments on the contribution of LEM‑4 in the regulation of protein phosphorylation and nuclear reformation.

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Figure 1. Model of the evolutionarily conserved regulatory mechanism controlling the function of BAF during cell cycle. During interphase BAF dimers (purple) bind LEM domain proteins (orange) of the INM and DNA to link the NE with the chromatin (blue). During mitotic entry the NE breaks down. At the nuclear periphery (prophase) and later on the condensed chromatin surface (prophase and metaphase) VRK-1 (red) phosphorylates BAF to keep it away from its binding partners. During mitotic exit (ana- and telophase) NE reforms around the decondensing chromatin. LEM-4 binds to VRK-1 and inhibits its enzymatic activity. Furthermore, LEM-4 also binds to a PP2A complex (green) and promotes its activity to dephosphorylate BAF. Consequently, BAF is recruited to the chromatin surface where it can bind LEM domain proteins to reform the NE.
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Figure 1: Figure 1. Model of the evolutionarily conserved regulatory mechanism controlling the function of BAF during cell cycle. During interphase BAF dimers (purple) bind LEM domain proteins (orange) of the INM and DNA to link the NE with the chromatin (blue). During mitotic entry the NE breaks down. At the nuclear periphery (prophase) and later on the condensed chromatin surface (prophase and metaphase) VRK-1 (red) phosphorylates BAF to keep it away from its binding partners. During mitotic exit (ana- and telophase) NE reforms around the decondensing chromatin. LEM-4 binds to VRK-1 and inhibits its enzymatic activity. Furthermore, LEM-4 also binds to a PP2A complex (green) and promotes its activity to dephosphorylate BAF. Consequently, BAF is recruited to the chromatin surface where it can bind LEM domain proteins to reform the NE.

Mentions: The nuclear envelope (NE) is a sub-domain of the endoplasmic reticulum (ER) double membrane system, which is specialized to passively separate chromatin from the cytoplasm and to actively regulate different nuclear events.1-3 The diverse functions of the NE are mediated by membrane-associated and integral membrane proteins of the NE. Some of these proteins are part of networks of interactions that reach from chromatin and lamin filaments in the nucleus to the cytoskeleton in the cytoplasm.4-6 Particularly, barrier-to-autointegration factor (BAF), an essential and highly conserved metazoan protein, is required to link the NE with the chromatin.7,8 BAF is known to bind specifically as a dimer to one LEM (LAP2/emerin/MAN1) domain9,10 of the inner nuclear membrane (INM) proteins and to two DNA helixes in a sequence-independent manner.11,12 Through these interactions, BAF contributes to the integrity of the NE (Fig. 1). Other linking proteins include HP-1, which in a similar manner, but through distinct interactions, also links the NE with the chromatin.1 This mechanism is however not conserved in all metazoa. Additionally, several integral INM proteins possess long basic domains that can mediate direct interactions between the NE and DNA.13


LEM-4 promotes rapid dephosphorylation of BAF during mitotic exit.

Gorjánácz M - Nucleus (2012)

Figure 1. Model of the evolutionarily conserved regulatory mechanism controlling the function of BAF during cell cycle. During interphase BAF dimers (purple) bind LEM domain proteins (orange) of the INM and DNA to link the NE with the chromatin (blue). During mitotic entry the NE breaks down. At the nuclear periphery (prophase) and later on the condensed chromatin surface (prophase and metaphase) VRK-1 (red) phosphorylates BAF to keep it away from its binding partners. During mitotic exit (ana- and telophase) NE reforms around the decondensing chromatin. LEM-4 binds to VRK-1 and inhibits its enzymatic activity. Furthermore, LEM-4 also binds to a PP2A complex (green) and promotes its activity to dephosphorylate BAF. Consequently, BAF is recruited to the chromatin surface where it can bind LEM domain proteins to reform the NE.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3585021&req=5

Figure 1: Figure 1. Model of the evolutionarily conserved regulatory mechanism controlling the function of BAF during cell cycle. During interphase BAF dimers (purple) bind LEM domain proteins (orange) of the INM and DNA to link the NE with the chromatin (blue). During mitotic entry the NE breaks down. At the nuclear periphery (prophase) and later on the condensed chromatin surface (prophase and metaphase) VRK-1 (red) phosphorylates BAF to keep it away from its binding partners. During mitotic exit (ana- and telophase) NE reforms around the decondensing chromatin. LEM-4 binds to VRK-1 and inhibits its enzymatic activity. Furthermore, LEM-4 also binds to a PP2A complex (green) and promotes its activity to dephosphorylate BAF. Consequently, BAF is recruited to the chromatin surface where it can bind LEM domain proteins to reform the NE.
Mentions: The nuclear envelope (NE) is a sub-domain of the endoplasmic reticulum (ER) double membrane system, which is specialized to passively separate chromatin from the cytoplasm and to actively regulate different nuclear events.1-3 The diverse functions of the NE are mediated by membrane-associated and integral membrane proteins of the NE. Some of these proteins are part of networks of interactions that reach from chromatin and lamin filaments in the nucleus to the cytoskeleton in the cytoplasm.4-6 Particularly, barrier-to-autointegration factor (BAF), an essential and highly conserved metazoan protein, is required to link the NE with the chromatin.7,8 BAF is known to bind specifically as a dimer to one LEM (LAP2/emerin/MAN1) domain9,10 of the inner nuclear membrane (INM) proteins and to two DNA helixes in a sequence-independent manner.11,12 Through these interactions, BAF contributes to the integrity of the NE (Fig. 1). Other linking proteins include HP-1, which in a similar manner, but through distinct interactions, also links the NE with the chromatin.1 This mechanism is however not conserved in all metazoa. Additionally, several integral INM proteins possess long basic domains that can mediate direct interactions between the NE and DNA.13

Bottom Line: We have identified LEM‑4, a conserved protein of the nuclear envelope, as an essential coordinator of kinase and phosphatase activities during mitotic exit.Inhibition of VRK‑1 kinase and promotion of a PP2A phosphatase complex by LEM‑4 tightly regulate the phosphorylation state of BAF, an essential player of nuclear reformation at the end of mitosis.Here I offer extended comments on the contribution of LEM‑4 in the regulation of protein phosphorylation and nuclear reformation.

View Article: PubMed Central - PubMed

Affiliation: European Molecular Biology Laboratory; Heidelberg, Germany. gorjanac@embl.de

ABSTRACT
The transitions between the successive cell cycle stages depend on reversible protein phosphorylation events. The phosphorylation state of every protein within a cell is strictly determined by spatiotemporally controlled kinase and phosphatase activities. Nuclear disassembly and reassembly during open mitosis in higher eukaryotic cells is one such process that is tightly regulated by the reversible phosphorylation of key proteins. However, little is known about the regulation of these mitotic events. In particular, although kinase function during entry into mitosis is better studied, very little is known about how proteins are dephosphorylated to allow nuclear reformation at the end of mitosis. We have identified LEM‑4, a conserved protein of the nuclear envelope, as an essential coordinator of kinase and phosphatase activities during mitotic exit. Inhibition of VRK‑1 kinase and promotion of a PP2A phosphatase complex by LEM‑4 tightly regulate the phosphorylation state of BAF, an essential player of nuclear reformation at the end of mitosis. Here I offer extended comments on the contribution of LEM‑4 in the regulation of protein phosphorylation and nuclear reformation.

Show MeSH
Related in: MedlinePlus