Activation of MKK6, an upstream activator of p38, in Alzheimer's disease

Zhu, Xiongwei; Rottkamp, Catherine A.; Hartzler, Anthony W.; Sun, Zheng; Takeda, Atsushi; Boux, Heather; Shimohama, Shun; Perry, George; Smith, Mark A.

doi:10.1046/j.1471-4159.2001.00597.x

Cited by 149 publications

(69 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Significantly, recent findings have provided strong evidence that the p38 MAPK signaling cascade is overactivated in AD (Zhu et al, 2001;Johnson and Bailey, 2003;Sun et al, 2003). These results underscore the disease relevance of our observation of the regulation of PAR-1 and tau phosphorylation by osmotic stress.…”

Section: Discussionsupporting

confidence: 81%

Activation of PAR-1 Kinase and Stimulation of Tau Phosphorylation by Diverse Signals Require the Tumor Suppressor Protein LKB1

Wang

Imai²,

Lu³

2007

J. Neurosci.

View full text Add to dashboard Cite

Aberrant phosphorylation of tau is associated with a number of neurodegenerative diseases, including Alzheimer's disease (AD). The molecular mechanisms by which tau phosphorylation is regulated under normal and disease conditions are not well understood. Microtubule affinity regulating kinase (MARK) and PAR-1 have been identified as physiological tau kinases, and aberrant phosphorylation of MARK/PAR-1 target sites in tau has been observed in AD patients and animal models. Here we show that phosphorylation of PAR-1 by the tumor suppressor protein LKB1 is required for PAR-1 activation, which in turn promotes tau phosphorylation in Drosophila. Diverse stress stimuli, such as high osmolarity and overexpression of the human ␤-amyloid precursor protein, can promote PAR-1 activation and tau phosphorylation in an LKB1-dependent manner. These results reveal a new function for the tumor suppressor protein LKB1 in a signaling cascade through which the phosphorylation and function of tau is regulated by diverse signals under physiological and pathological conditions.

show abstract

Section: Discussionsupporting

confidence: 81%

Activation of PAR-1 Kinase and Stimulation of Tau Phosphorylation by Diverse Signals Require the Tumor Suppressor Protein LKB1

Wang

Imai²,

Lu³

2007

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…The finding that Rac1-GTP levels were altered in brain, but not muscle, also supports cell specificity to the function of MKK6 as a potential Rac1-GAP. In this context, it is interesting to note that MKK6 activation has been linked to a number of neurodegenerative diseases with known components of oxidative stress (21,39,53). H 2 O 2 is known to act as a second messenger of tyrosine phosphorylation signaling pathways by reversibly inactivating tyrosine phosphatases (42).…”

Section: Discussionmentioning

confidence: 99%

MKK6 Phosphorylation Regulates Production of Superoxide by Enhancing Rac GTPase Activity

Harraz

Park

Abbott

et al. 2007

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

Rac-dependent NADPH oxidases generate reactive oxygen species used in cell signaling and microbial killing or both. Whereas the mechanisms leading to NADPH oxidase activation are fairly well studied, the mechanisms that control downregulation of this enzyme complex remain unclear. We hypothesized that reactive oxygen species produced by NADPH oxidase may autoregulate the complex by inhibiting Rac activity. To this end, we searched for binding partners of Rac1 and identified a tyrosine-phosphorylated fragment of MKK6 that bound to Rac1 under redox-stress conditions. Constitutively active MKK6 interacted directly with Rac1 in vitro, and this interaction was enhanced when MKK6 was phosphorylated on tyrosine 219. Both Rac1 and Rac2 immunoprecipitated an MKK6 fragment under conditions that elevate cellular peroxide levels in 293 and RAW cells, respectively. Constitutively active and wild-type MKK6 enhanced Rac-GTPase activity in vitro, and their overexpression inhibited PMA-induced NADPH oxidase activation in RAW cells. In contrast, a Y219F mutant of MKK6 only partially enhanced Rac1 GTPase activity, and its overexpression did not alter PMA-induced NADPH oxidase activation in RAW cells. Last, MKK6 deficiency led to an increase in Rac1-GTP levels in brain tissue. Our findings suggest that MKK6 downregulates NADPH oxidase activity by enhancing Rac-GTPase activity.

show abstract

“…MAPK pathways, such as the extracellular signal regulated MAP kinase (ERK) 1/2 pathway (8,32,33), the c-Jun-N-terminal kinase (JNK) pathway (8,34,35) and the p38 (8,36) pathway, are activated in the brains of AD patients. JKK1 and MKK6, upstream activators of JNK and p38, respectively, are also activated in AD individuals (37,38). All three MAPK pathways mentioned above phosphorylate Tau protein in vitro (39)(40)(41) while the activation of JNK and p38, specifically, was associated with age-dependent amyloid pla-http://bmbreports.org BMB reports que deposition in a Tg2576/PS1 double transgenic AD mouse model (42).…”

Section: The Role Of Mapk In Admentioning

confidence: 99%