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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 signalling downstream of receptor tyrosine kinases (RTK). RAS activation initiates PAK1, RAF/mitogen activated protein kinase (MAPK) and phospoinositide 3-kinase (PI3K)/AKT signalling. Activation of PAK1 by epidermal growth factor induces its nuclear translocation. PAK1 activation by RAS may provide a positive feedback loop to further activate MAPK and PI3K. Importantly, PAK1 allocates crosstalk between the PI3K and MAPK pathways. PAK1 may induce MEK1/2 or ERK1/2 independent of RAF, as well as increase PI3K/AKT signalling by scaffolding PDK1 to increase phosphorylation of AKT. In turn, PDK1 may also directly phosphorylate and activate PAK1. PAK1 signalling may activate pro-inflammatory or pro-survival pathways by facilitating nuclear activation of NF-κB.
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GUTJNL2014306768F2: P-21 activated kinase (PAK)1 signalling downstream of receptor tyrosine kinases (RTK). RAS activation initiates PAK1, RAF/mitogen activated protein kinase (MAPK) and phospoinositide 3-kinase (PI3K)/AKT signalling. Activation of PAK1 by epidermal growth factor induces its nuclear translocation. PAK1 activation by RAS may provide a positive feedback loop to further activate MAPK and PI3K. Importantly, PAK1 allocates crosstalk between the PI3K and MAPK pathways. PAK1 may induce MEK1/2 or ERK1/2 independent of RAF, as well as increase PI3K/AKT signalling by scaffolding PDK1 to increase phosphorylation of AKT. In turn, PDK1 may also directly phosphorylate and activate PAK1. PAK1 signalling may activate pro-inflammatory or pro-survival pathways by facilitating nuclear activation of NF-κB.

Mentions: Receptor tyrosine kinase activation of RAS leads to the activation of multiple signalling cascades, including the activation of PAK1.1 Inversely, PAK1 knockout (KO) mice (which have no distinct phenotype) display reduced expression of RAS key effectors including ERK and AKT within the colon.6364 PAK4 KO mice are embryonically lethal.65 Cellular knockdown of PAK4 also impeded ERK signalling in vitro.66 PAK1 activates mitogen activated protein kinase (MAPK)/ERK signalling via phosphorylation of RAF, MEK and ERK, as well as forming protein–protein interactions in the absence of its kinase activity.6768 PAK4 is located downstream of AKT;43 however, PAK1 is centralised between RAS and PI3K/AKT. Within the PI3K/AKT cascade, PAK1 plays another key role via scaffolding PDK1, thereby facilitating phosphorylation of AKT.69 In a positive feedback loop, both PDK1 and AKT phosphorylate and activate PAK13770 (figure 2).


Republished: tracing PAKs from GI inflammation to cancer.

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

P-21 activated kinase (PAK)1 signalling downstream of receptor tyrosine kinases (RTK). RAS activation initiates PAK1, RAF/mitogen activated protein kinase (MAPK) and phospoinositide 3-kinase (PI3K)/AKT signalling. Activation of PAK1 by epidermal growth factor induces its nuclear translocation. PAK1 activation by RAS may provide a positive feedback loop to further activate MAPK and PI3K. Importantly, PAK1 allocates crosstalk between the PI3K and MAPK pathways. PAK1 may induce MEK1/2 or ERK1/2 independent of RAF, as well as increase PI3K/AKT signalling by scaffolding PDK1 to increase phosphorylation of AKT. In turn, PDK1 may also directly phosphorylate and activate PAK1. PAK1 signalling may activate pro-inflammatory or pro-survival pathways by facilitating nuclear activation of NF-κB.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

GUTJNL2014306768F2: P-21 activated kinase (PAK)1 signalling downstream of receptor tyrosine kinases (RTK). RAS activation initiates PAK1, RAF/mitogen activated protein kinase (MAPK) and phospoinositide 3-kinase (PI3K)/AKT signalling. Activation of PAK1 by epidermal growth factor induces its nuclear translocation. PAK1 activation by RAS may provide a positive feedback loop to further activate MAPK and PI3K. Importantly, PAK1 allocates crosstalk between the PI3K and MAPK pathways. PAK1 may induce MEK1/2 or ERK1/2 independent of RAF, as well as increase PI3K/AKT signalling by scaffolding PDK1 to increase phosphorylation of AKT. In turn, PDK1 may also directly phosphorylate and activate PAK1. PAK1 signalling may activate pro-inflammatory or pro-survival pathways by facilitating nuclear activation of NF-κB.
Mentions: Receptor tyrosine kinase activation of RAS leads to the activation of multiple signalling cascades, including the activation of PAK1.1 Inversely, PAK1 knockout (KO) mice (which have no distinct phenotype) display reduced expression of RAS key effectors including ERK and AKT within the colon.6364 PAK4 KO mice are embryonically lethal.65 Cellular knockdown of PAK4 also impeded ERK signalling in vitro.66 PAK1 activates mitogen activated protein kinase (MAPK)/ERK signalling via phosphorylation of RAF, MEK and ERK, as well as forming protein–protein interactions in the absence of its kinase activity.6768 PAK4 is located downstream of AKT;43 however, PAK1 is centralised between RAS and PI3K/AKT. Within the PI3K/AKT cascade, PAK1 plays another key role via scaffolding PDK1, thereby facilitating phosphorylation of AKT.69 In a positive feedback loop, both PDK1 and AKT phosphorylate and activate PAK13770 (figure 2).

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