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Republished: tracing PAKs from GI inflammation to cancer.

Dammann K, Khare V, Gasche C - Postgrad Med J (2014)

Bottom Line: P-21 activated kinases (PAKs) are effectors of Rac1/Cdc42 which coordinate signals from the cell membrane to the nucleus.Activation of PAKs drive important signalling pathways including mitogen activated protein kinase, phospoinositide 3-kinase (PI3K/AKT), NF-κB and Wnt/β-catenin.Intestinal PAK1 expression increases with inflammation and malignant transformation, although the biological relevance of PAKs in the development and progression of GI disease is only incompletely understood.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine III, Division of Gastroenterology and Hepatology and Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria.

No MeSH data available.


Related in: MedlinePlus

P-21 activated kinase (PAK)1 facilitates Wnt/β-catenin signalling. (A) In the absence of the Wnt ligand, β-catenin signalling is regulated and β-catenin is degraded through a multiprotein destruction complex. (B) Upon binding of the Wnt ligand to the membrane-bound Frizzled receptor, β-catenin accumulates in the cytoplasm and translocates to the nucleus. Phosphorylation of β-catenin by PAK1 within the cytoplasm occurs at two different residues, Ser-663 (red) and Ser-675 (blue), although only Ser-663 is specific to PAK1. As a consequence, β-catenin stability, nuclear translocation and transcriptional activity are increased. (C) In the absence of PAK1 activity, β-catenin is restored at adherens junction (AJ) where it anchors E-cadherin to the cytoskeleton through an interaction with α-catenin.
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GUTJNL2014306768F3: P-21 activated kinase (PAK)1 facilitates Wnt/β-catenin signalling. (A) In the absence of the Wnt ligand, β-catenin signalling is regulated and β-catenin is degraded through a multiprotein destruction complex. (B) Upon binding of the Wnt ligand to the membrane-bound Frizzled receptor, β-catenin accumulates in the cytoplasm and translocates to the nucleus. Phosphorylation of β-catenin by PAK1 within the cytoplasm occurs at two different residues, Ser-663 (red) and Ser-675 (blue), although only Ser-663 is specific to PAK1. As a consequence, β-catenin stability, nuclear translocation and transcriptional activity are increased. (C) In the absence of PAK1 activity, β-catenin is restored at adherens junction (AJ) where it anchors E-cadherin to the cytoskeleton through an interaction with α-catenin.

Mentions: The Wnt/β-catenin pathway is a key process in GI development and homeostasis.71 Intestinal LGR5+ stem cells use Wnt signalling for continual regeneration.7172 β-Catenin is the key effector of the Wnt signal, and regulates transcription of Wnt target genes when bound to the T cell factor (TCF) or lymphoid enhancer factor (LEF) family of transcription factors. Importantly, β-catenin drives canonical Wnt signalling through Rac1.73 The Rac1 effector, PAK1, directly interacts with β-catenin and regulates its transcriptional activity through phosphorylation at Ser-663 and Ser-6751374 (figure 3). PAK1 KO mice in an adenomatous polyposis coli (APC) wildtype background displayed a marked reduction in nuclear β-catenin expression.63 PAK4 phosphorylates β-catenin at ser-675, and colocalises with β-catenin in the nucleus thereby increasing TCF/LEF transcriptional activation.59 β-Catenin is an effector of Wnt, and plays a role in cell-to-cell contacts as a complex with E-cadherin at AJ.75 Inhibition of PAK1 increased the membranous localisation of both β-catenin and E-cadherin,76 thereby increasing the formation of AJ and reducing intestinal permeability. This further underlines the role of PAK1 in intestinal integrity and mucosal barrier function.


Republished: tracing PAKs from GI inflammation to cancer.

Dammann K, Khare V, Gasche C - Postgrad Med J (2014)

P-21 activated kinase (PAK)1 facilitates Wnt/β-catenin signalling. (A) In the absence of the Wnt ligand, β-catenin signalling is regulated and β-catenin is degraded through a multiprotein destruction complex. (B) Upon binding of the Wnt ligand to the membrane-bound Frizzled receptor, β-catenin accumulates in the cytoplasm and translocates to the nucleus. Phosphorylation of β-catenin by PAK1 within the cytoplasm occurs at two different residues, Ser-663 (red) and Ser-675 (blue), although only Ser-663 is specific to PAK1. As a consequence, β-catenin stability, nuclear translocation and transcriptional activity are increased. (C) In the absence of PAK1 activity, β-catenin is restored at adherens junction (AJ) where it anchors E-cadherin to the cytoskeleton through an interaction with α-catenin.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4222351&req=5

GUTJNL2014306768F3: P-21 activated kinase (PAK)1 facilitates Wnt/β-catenin signalling. (A) In the absence of the Wnt ligand, β-catenin signalling is regulated and β-catenin is degraded through a multiprotein destruction complex. (B) Upon binding of the Wnt ligand to the membrane-bound Frizzled receptor, β-catenin accumulates in the cytoplasm and translocates to the nucleus. Phosphorylation of β-catenin by PAK1 within the cytoplasm occurs at two different residues, Ser-663 (red) and Ser-675 (blue), although only Ser-663 is specific to PAK1. As a consequence, β-catenin stability, nuclear translocation and transcriptional activity are increased. (C) In the absence of PAK1 activity, β-catenin is restored at adherens junction (AJ) where it anchors E-cadherin to the cytoskeleton through an interaction with α-catenin.
Mentions: The Wnt/β-catenin pathway is a key process in GI development and homeostasis.71 Intestinal LGR5+ stem cells use Wnt signalling for continual regeneration.7172 β-Catenin is the key effector of the Wnt signal, and regulates transcription of Wnt target genes when bound to the T cell factor (TCF) or lymphoid enhancer factor (LEF) family of transcription factors. Importantly, β-catenin drives canonical Wnt signalling through Rac1.73 The Rac1 effector, PAK1, directly interacts with β-catenin and regulates its transcriptional activity through phosphorylation at Ser-663 and Ser-6751374 (figure 3). PAK1 KO mice in an adenomatous polyposis coli (APC) wildtype background displayed a marked reduction in nuclear β-catenin expression.63 PAK4 phosphorylates β-catenin at ser-675, and colocalises with β-catenin in the nucleus thereby increasing TCF/LEF transcriptional activation.59 β-Catenin is an effector of Wnt, and plays a role in cell-to-cell contacts as a complex with E-cadherin at AJ.75 Inhibition of PAK1 increased the membranous localisation of both β-catenin and E-cadherin,76 thereby increasing the formation of AJ and reducing intestinal permeability. This further underlines the role of PAK1 in intestinal integrity and mucosal barrier function.

Bottom Line: P-21 activated kinases (PAKs) are effectors of Rac1/Cdc42 which coordinate signals from the cell membrane to the nucleus.Activation of PAKs drive important signalling pathways including mitogen activated protein kinase, phospoinositide 3-kinase (PI3K/AKT), NF-κB and Wnt/β-catenin.Intestinal PAK1 expression increases with inflammation and malignant transformation, although the biological relevance of PAKs in the development and progression of GI disease is only incompletely understood.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine III, Division of Gastroenterology and Hepatology and Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria.

No MeSH data available.


Related in: MedlinePlus