Phosphorylation of tau by death-associated protein kinase 1 antagonizes the kinase-induced cell apoptosis.
The intracellular accumulation of hyperphosphorylated tau plays a crucial role in neurodegeneration of Alzheimer's disease (AD), but the mechanism is not fully understood. From the observation that tau hyperphosphorylation renders cells more resistant to chemically-induced cell apoptosis, we have proposed that tau-involved apoptotic abortion may be the trigger of neurodegeneration. Here, we further studied whether this phenomenon is also applicable for the cell death induced by constitutively expressed factors, such as death-associated protein kinase 1 (DAPK1). We found that DAPK1 was upregulated and accumulated in the brain of human tau transgenic mice. Overexpression of DAPK1 in HEK293 and N2a cells decreased cell viability with activation of caspase-3, whereas simultaneous expression of tau antagonized DAPK1-induced apoptotic cell death. Expression of DAPK1 induced tau hyperphosphorylation at Thr231, Ser262, and Ser396 with no effects on protein phosphatase 2A, glycogen synthase kinase-3β, protein kinase A, calcium/calmodulin dependent protein kinase II, cell division cycle 2, or cyclin dependent protein kinase 5. The phosphorylation level of microtubule affinity-regulating kinase 2 (MARK2) was increased by expression of DAPK1, but simultaneous downregulation of MARK2 did not affect the DAPK1-induced tau hyperphosphorylation. DAPK1 was co-immunoprecipitated with tau proteins both in vivo and in vitro, and expression of the kinase domain-truncated DAPK1 did not induce tau hyperphosphorylation. These data suggest that tau hyperphosphorylation at Thr231, Ser262, and Ser396 by DAPK1 renders the cells more resistant to the kinase-induced apoptotic cell death, providing new insights into the tau-involved apoptotic abortion in the course of chronic neurodegeneration.
Department of Pathophysiology, Key Laboratory of the Ministry Education of China for Neurological Disease, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.
Dong-Xiao
DX
Duan
Gao-Shang
GS
Chai
Zhong-Fei
ZF
Ni
Yu
Y
Hu
Yu
Y
Luo
Xiang-Shu
XS
Cheng
Ning-Ning
NN
Chen
Jian-Zhi
JZ
Wang
Gong-Ping
GP
Liu
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001921:Brain / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D064550:Death-Associated Protein Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics; D016875:tau Proteins / Q000032:analysis / Q000378:metabolism*
C054369:MAPT protein, human; D016875:tau Proteins; C579096:DAPK1 protein, human; D064550:Death-Associated Protein Kinases
Alzheimer's disease; apoptosis; death-associated protein kinase 1 (DAPK1); tau phosphorylation