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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 in canonical and non-canonical NF-κB signalling. NF-κB signalling regulates transcription of target genes via two separate cascades known as the canonical and non-canonical pathways. In the canonical pathway, TNFα elicits PAK1 and c-Jun N-terminal kinase (JNK) phosphorylation. Subsequent phosphorylation of IKKα/β by JNK initiates phosphorylation of IκB. Consequently, RelA is released from the IκB complex and translocates into the nucleus. IκB is tagged by ubiquitin for proteasomal degradation. LPS is a known activator of non-canonical NF-κB signalling. LPS may elicit PAK1 activation through an unknown mechanism. PAK1 phosphorylates and activates NF-κB interacting kinase (NIK), which activates IKKα. In turn, IKKα phosphorylates p100 and the p100–RelB complex is released. P100 is processed into p52 which dimerises with RelB and translocates to the nucleus to activate target genes.
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GUTJNL2014306768F4: P-21 activated kinase (PAK)1 in canonical and non-canonical NF-κB signalling. NF-κB signalling regulates transcription of target genes via two separate cascades known as the canonical and non-canonical pathways. In the canonical pathway, TNFα elicits PAK1 and c-Jun N-terminal kinase (JNK) phosphorylation. Subsequent phosphorylation of IKKα/β by JNK initiates phosphorylation of IκB. Consequently, RelA is released from the IκB complex and translocates into the nucleus. IκB is tagged by ubiquitin for proteasomal degradation. LPS is a known activator of non-canonical NF-κB signalling. LPS may elicit PAK1 activation through an unknown mechanism. PAK1 phosphorylates and activates NF-κB interacting kinase (NIK), which activates IKKα. In turn, IKKα phosphorylates p100 and the p100–RelB complex is released. P100 is processed into p52 which dimerises with RelB and translocates to the nucleus to activate target genes.

Mentions: Rac1 is also a key activator of the NF-κB, which orchestrates a cellular inflammatory response and promotes tumourigenesis.7778 Tumour necrosis factor (TNF)α or interleukin (IL)-1β stimulate canonical NF-κB signalling, whereas, lipopolysaccharide (LPS) or lymphotoxin B activates the non-canonical pathway (figure 4).79 LPS has been shown to activate both canonical and non-canonical NF-κB, albeit through different cascades.80 Both pathways regulate transcription of multiple genes which activate or suppress proliferation, apoptosis or cytokine production. Activation of NF-κB has also been correlated to mucosal barrier dysfunction8182 further implicating the importance of NF-κB in GI homeostasis.


Republished: tracing PAKs from GI inflammation to cancer.

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

P-21 activated kinase (PAK)1 in canonical and non-canonical NF-κB signalling. NF-κB signalling regulates transcription of target genes via two separate cascades known as the canonical and non-canonical pathways. In the canonical pathway, TNFα elicits PAK1 and c-Jun N-terminal kinase (JNK) phosphorylation. Subsequent phosphorylation of IKKα/β by JNK initiates phosphorylation of IκB. Consequently, RelA is released from the IκB complex and translocates into the nucleus. IκB is tagged by ubiquitin for proteasomal degradation. LPS is a known activator of non-canonical NF-κB signalling. LPS may elicit PAK1 activation through an unknown mechanism. PAK1 phosphorylates and activates NF-κB interacting kinase (NIK), which activates IKKα. In turn, IKKα phosphorylates p100 and the p100–RelB complex is released. P100 is processed into p52 which dimerises with RelB and translocates to the nucleus to activate target genes.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

GUTJNL2014306768F4: P-21 activated kinase (PAK)1 in canonical and non-canonical NF-κB signalling. NF-κB signalling regulates transcription of target genes via two separate cascades known as the canonical and non-canonical pathways. In the canonical pathway, TNFα elicits PAK1 and c-Jun N-terminal kinase (JNK) phosphorylation. Subsequent phosphorylation of IKKα/β by JNK initiates phosphorylation of IκB. Consequently, RelA is released from the IκB complex and translocates into the nucleus. IκB is tagged by ubiquitin for proteasomal degradation. LPS is a known activator of non-canonical NF-κB signalling. LPS may elicit PAK1 activation through an unknown mechanism. PAK1 phosphorylates and activates NF-κB interacting kinase (NIK), which activates IKKα. In turn, IKKα phosphorylates p100 and the p100–RelB complex is released. P100 is processed into p52 which dimerises with RelB and translocates to the nucleus to activate target genes.
Mentions: Rac1 is also a key activator of the NF-κB, which orchestrates a cellular inflammatory response and promotes tumourigenesis.7778 Tumour necrosis factor (TNF)α or interleukin (IL)-1β stimulate canonical NF-κB signalling, whereas, lipopolysaccharide (LPS) or lymphotoxin B activates the non-canonical pathway (figure 4).79 LPS has been shown to activate both canonical and non-canonical NF-κB, albeit through different cascades.80 Both pathways regulate transcription of multiple genes which activate or suppress proliferation, apoptosis or cytokine production. Activation of NF-κB has also been correlated to mucosal barrier dysfunction8182 further implicating the importance of NF-κB in GI homeostasis.

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