33) JNK pathway is activated by a large number of external stimuli, and the initial signaling pathway starts with the activation of several MAPKKKs including TAK1, MEKK1/4, MLK-2 and -3, and ASK1
, which phosphorylate MEK4 or MEK7 and induce the activation of JNK.
In this review, we briefly summarise the regulatory mechanisms behind ASK1 signaling (reviewed in detail elsewhere (2) and then focus on the roles of ASK1 in various diseases, mainly as demonstrated by analyses of ASK1-deficient mice.
ASK1 was identified as a MAP3K that activates the MAP kinase kinase 4 (MKK4)/MKK7-JNK and MKK3/MKK6-p38 pathways.
It has been reported that ASK1 activity is regulated by many ASK1-interacting proteins, (2) among which thioredoxin (Trx) plays an important role.
ASK2 is unstable and inactive in ASK1-deficient cells, suggesting that ASK1 is necessary for ASK2 stabilisation and activation.
Posttranslational modifications, including phosphorylation, play a critical role in regulation of ASK1 activity.
This inhibitory effect of HSF-1 overexpression is cancelled by ASK1 overexpression, suggesting that ASK1 is negatively regulated by HSF-1 in [H.
ASK1 may also play a role in the kidney, where IR has been shown to induce kidney injury, as ASK1 is activated in response to hypoxia and induces apoptosis in renal tubule epithelial cells.
These findings suggest that ASK1 plays a critical role in the pathogenesis of ventricular remodelling by promoting apoptosis or cardiomyocyte hypertrophy.
Small G-proteins Rac1 and cdc42 activate ASK1
, MLK3, and MLK3 that directly activate MKK3 and MKK6 which phosphorylates p38 on both tyrosine and threonine residue resulting in the activation of p38 pathway [68, 69].