Osmotic Stress Activates the TAK1-JNK Pathway While Blocking TAK1-mediated NF-κB Activation

Abstract

Osmotic stress activates MAPKs, including JNK and p38, which play important roles in cellular stress responses. Transforming growth factor-␤-activated kinase 1 (TAK1) is a member of the MAPK kinase kinase (MAPKKK) family and can activate JNK and p38. TAK1 can also activate IB kinase (IKK) that leads to degradation of IB and subsequent NF-B activation. We found that TAK1 is essential for osmotic stress-induced activation of JNK but is not an exclusive mediator of p38 activation. Furthermore, we found that although TAK1 was highly activated upon osmotic stress, it could not induce degradation of IB or activation of NF-B. These results suggest that TAK1 activity is somehow modulated to function specifically in osmotic stress signaling, leading to the activation of JNK but not of IKK. To elucidate the mechanism underlying this modulation, we screened for potential TAK1-binding proteins. We found that TAO2 (thousand-and-one amino acid kinase 2) associates with TAK1 and can inhibit TAK1-mediated activation of NF-B but not of JNK. We observed that TAO2 can interfere with the interaction between TAK1 and IKK and thus may regulate TAK1 function. TAK1 is activated by many distinct stimuli, including cytokines and stresses, and regulation by TAO2 may be important to activate specific intracellular signaling pathways that are unique to osmotic stress.

Germinal center kinases in immune regulation

“…For example, TAO2 can associate with TGF-b activated kinase 1 (TAK1) to inhibit TAK1-mediated activation of NF-kB. 129 TAO2 may regulate TAK1 function through interfering with the interaction between TAK1 and IkappaB kinase. Furthermore, TAO2 does not inhibit the activation of JNK by TAK1, suggesting that TAO2 regulation of TAK1 is important to activate specific intracellular signaling pathways.…”

MAP3Ks as central regulators of cell fate during development

“…TAOk1 interacts with and activates MKK3 leading to activation of p38 (Hutchison et al, 1998). TAOk2 negatively regulates TAK1 activation of the NF B pathway after osmotic stress (Huangfu et al, 2006). TAOk2 associates with MKK3 and MKK6, MAP2Ks upstream of p38 (Chen and Cobb, 2001).…”

Osmotic stress blocks NF‐κB‐dependent inflammatory responses by inhibiting ubiquitination of IκB

“…Human embryonic kidney 293 cells, 293 IL-1RI cells that stably express the IL-1 receptor I [15] were maintained as described previously [14]. Mouse keratinocytes were described previously [16].…”

“…We have previously shown that the TAO2 kinase can interfere with the interaction of TAK1 and IKK, resulting in the inhibition of the NF-jB pathway. However, knockdown of TAO2 was observed to have only a partial effect on relieving inhibition of NF-jB [14]. This suggests that NF-jB activation is blocked by additional mechanisms that function under conditions of osmotic stress.…”

“…The most upstream components of the MAPK cascades are MAPK kinase kinases (MAP3Ks), and a sub-group of MAP3Ks including TAK1 and MEKKs can activate not only MAPK cascades but also IKK, leading to NF-jB activation [12,13]. However, even though osmotic stress strongly activates MEKKs and TAK1, activation of NF-jB is normally undetectable under osmotic stress conditions [14]. Therefore, it seemed likely that there is an inhibitory mechanism that blocks NF-jB activation under conditions of osmotic stress.…”