Functional inactivation of a transcriptional corepressor by a signaling kinase

Barnes, Christopher J.; Vadlamudi, Ratna K.; Mishra, Sandip K.; Jacobson, Raymond H.; Li, Feng; Kumar, Rakesh

doi:10.1038/nsb957

Cited by 94 publications

(93 citation statements)

References 26 publications

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“…We first tested the ability of PAK1 to phosphorylate wild-type GST-Ebp1 and Ebp1 deletion constructs. Purified PAK1 enzyme phosphorylated full-length GST-Ebp1 and was autophosphorylated as reported (Barnes et al, 2003a) (Figure 1A). We next used GSTEbp1 deletion constructs ( Figure 1B) were created in wild-type GST-Ebp1.…”

Section: Erbb3 Binding Protein Is a Substrate Of Pak1supporting

confidence: 66%

“…Thus, data reported here strengthen the role of PAK1 in corepressor regulation. P21-activated kinase 1 inactivates the transcriptional corepressor CtBP, due to the changes in its cellular localisation (Barnes et al, 2003a). Conversely, the activity of the Notch pathway repressor SHARP is enhanced by PAK1 phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

“…In vitro kinase assays were performed as described previously (Barnes et al, 2003b). Briefly, GST-tagged Ebp1 proteins were used as substrates.…”

Section: P21-activated Kinase 1 Assaymentioning

confidence: 99%

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Phosphorylation of the ErbB3 binding protein Ebp1 by p21-activated kinase 1 in breast cancer cells

et al. 2008

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The ErbB3 binding protein (Ebp1) is a transcriptional corepressor that inhibits the activity of proliferation-associated genes and the growth of human breast cancer cell lines. Treatment of breast cancer cells with the ErbB3 ligand heregulin (HRG) results in increased phosphorylation of Ebp1 and transcriptional repression. The p21-activated serine/threonine kinase 1 (PAK1), which plays an important role in breast cancer progression and resistance to the anti-oestrogen tamoxifen, is also activated by HRG. We therefore examined the ability of PAK1 to phosphorylate and regulate the function of Ebp1. We found that PAK1 phosphorylated Ebp1 in vitro and mapped the phosphorylation site to threonine 261. Both HRG treatment and expression of a constitutively activated PAK1 in MCF-7 breast cancer cells enhanced threonine phosphorylation of Ebp1. In MCF-7 cells, ectopically expressed Ebp1 bound endogenous PAK1 and this association was enhanced by treatment with HRG. Mutation of the PAK1 phosphorylation site to glutamic acid, mimicking a phosphorylated state, completely abrogated the ability of Ebp1 to repress transcription, inhibit growth of breast cancer cell lines and contribute to tamoxifen sensitivity. These studies demonstrate for the first time that Ebp1 is a substrate of PAK1 and the importance of the PAK1 phosphorylation site for the functional activity of Ebp1 in breast cancer cells.

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Section: Erbb3 Binding Protein Is a Substrate Of Pak1supporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

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Phosphorylation of the ErbB3 binding protein Ebp1 by p21-activated kinase 1 in breast cancer cells

et al. 2008

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“…An increase in PGM activity was correlated with higher Pak1 and PGM expression in the MDA-MB-435 cells. When Pak1-specific siRNA (Barnes et al, 2003) was transfected to downregulate Pak1 expression, PGM activity was reduced by 40% in MCF-7 cells and 30% in MDA-MB-435 cells (Figure 6b). Since the experiment was carried out in the presence of 10% serum, the results indicate that, under physiological conditions, Pak1 is required for PGM activity.…”

Section: Pgm Regulation By Pak1 Signalingmentioning

confidence: 99%

Regulation of phosphoglucomutase 1 phosphorylation and activity by a signaling kinase

et al. 2004

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We have identified a novel mechanism of cross-talk between cell signaling and metabolic pathways, whereby the signaling kinase p21-activated kinase 1 (Pak1) binds to, phosphorylates and enhances the enzymatic activity of phosphoglucomutase 1 (PGM), an important regulatory enzyme in cellular glucose utilization and energy homeostasis. Pak1 and PGM were colocalized in model cell systems and showed functional interactions in a physiological setting. Strong direct interaction of PGM with Pak1 but not Pak2, Pak3, or Pak4 was observed. PGM binding was within 75-149 amino acids (aa) of Pak1, while Pak1 binding to PGM was in the N-terminal 96 aa. Pak1-mediated phosphorylation of PGM selectively on threonine 466 significantly increased PGM enzymatic activity and could be blocked by transfection with a dominantnegative Pak1 expression vector and by Pak1-specific small inhibitory RNA. Stable transfection of PGM into PGM-deficient K-562 leukemia cells further demonstrated the role of Pak1 in regulating PGM activity. The results presented here provide new evidence that the cell signaling kinase Pak1 is a novel regulator of glucose metabolism through its phosphorylation and regulation of PGM activity. These findings suggest a new mechanism whereby growth factor signaling may coordinately integrate metabolic regulation with established signaling functions of cell cycle regulation and cell growth.

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“…PAK1, a kinase that is required for mitotic entry, has been shown to phosphorylate CtBP1-L isoform, but this modification has only been linked to the regulation of the co-repression activity of CtBP1. 65 Furthermore, as mentioned above, BARS is also a transcription co-repressor and its effect on the Golgi architecture needs to be formally dissociated from this function.…”

Section: The Golgi Mitotic Checkpoint Is Regulated By the Golgi Ribbomentioning

confidence: 99%

Golgi Ribbon Unlinking: An Organelle-Based G₂/M Checkpoint

Rabouille¹,

Kondylis²

2007

Cell Cycle

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Cell cycle checkpoints have been associated mostly with signaling mechanisms monitoring the genetic material for abnormalities and inaccuracy in partitioning, such as DNA lesions or failure in chromosome attachment to kinetochores. However, it becomes more evident that other checkpoints are turned on by cytoplasmic events, such as the cytoskeleton organization and the organelle structure. Here, we summarize recent evidence strongly suggesting that the integrity of the Golgi ribbon and more precisely the tubules interconnecting the Golgi stacks to form this ribbon, at late G 2 /early prophase, is linked to a Golgi-related G 2 /M checkpoint. A number of kinases phosphorylating a small subset of Golgi-localized proteins have been shown to promote the G 2 -specific Golgi ribbon unlinking, allowing the cell to enter mitosis. When these kinases are inactivated or when the substrates cannot be phosphorylated, Golgi unlinking is prevented and the cells are blocked or delayed in G 2 phase.

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Functional inactivation of a transcriptional corepressor by a signaling kinase

Cited by 94 publications

References 26 publications

Phosphorylation of the ErbB3 binding protein Ebp1 by p21-activated kinase 1 in breast cancer cells

Phosphorylation of the ErbB3 binding protein Ebp1 by p21-activated kinase 1 in breast cancer cells

Regulation of phosphoglucomutase 1 phosphorylation and activity by a signaling kinase

Golgi Ribbon Unlinking: An Organelle-Based G₂/M Checkpoint

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Functional inactivation of a transcriptional corepressor by a signaling kinase

Cited by 94 publications

References 26 publications

Phosphorylation of the ErbB3 binding protein Ebp1 by p21-activated kinase 1 in breast cancer cells

Phosphorylation of the ErbB3 binding protein Ebp1 by p21-activated kinase 1 in breast cancer cells

Regulation of phosphoglucomutase 1 phosphorylation and activity by a signaling kinase

Golgi Ribbon Unlinking: An Organelle-Based G2/M Checkpoint

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Product

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Golgi Ribbon Unlinking: An Organelle-Based G₂/M Checkpoint