Crosstalk between PSD-95 and JIP1-mediated signaling modules: the mechanism of MLK3 activation in cerebral ischemia.
Our previous study indicates that global ischemia facilitates the assembly of the GluR6.PSD-95.MLK3 signaling module, which in turn activated MLK3, leading to exacerbated ischemic neuron death. In addition, JIP1, functioning as a scaffold protein, could couple MLK3-MKK7-JNK to form a specific signaling module and facilitate the activation of the JNK signal pathway. However, the organization, regulation, and function between the two signaling modules and the effects they have on MLK3 activation remain incompletely understood. Here, we show that JIP1 maintains MLK3 in an inactive and monomeric state; once activated, MLK3 binds to PSD-95 and then dimerizes and autophosphorylates. In addition, a GluR6 C-terminus-containing peptide (Tat-GluR6-9c) and antisense oligonucleotides (AS-ODNs) against PSD-95 inhibit the integration of PSD-95 and MLK3 and the dimerization of MLK3, facilitate the interaction of JIP1 and MLK3, and, consequently, perform neuroprotection on neuron death. However, AS-ODNs against JIP1 play a negative role compared to that mentioned above. The findings show that the crosstalk occurs between PSD-95 and the JIP1-mediated signaling module, which may be involved in brain ischemic injury and contribute to the regulation of MLK3 activation. Thus, specific blockade of PSD-95-MLK3 coupling may reduce the extent of ischemia-reperfusion-induced neuronal cell death.
Zhang
Qing-Xiu
QX
Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, Xuzhou 221002, China.
Pei
Dong-Sheng
DS
Guan
Qiu-Hua
QH
Sun
Ya-Feng
YF
Liu
Xiao-Mei
XM
Zhang
Guang-Yi
GY
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D002545:Brain Ischemia / Q000503:physiopathology*; D019281:Dimerization; D000076122:Disks Large Homolog 4 Protein; D015696:Gene Products, tat / Q000494:pharmacology; D006624:Hippocampus / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D048688:MAP Kinase Kinase 7 / Q000502:physiology; D020930:MAP Kinase Kinase Kinases / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D008954:Models, Biological; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018092:Kainic Acid Receptors / Q000502:physiology; D015427:Reperfusion Injury / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; D000097806:GluK2 Kainate Receptor
D048868:Adaptor Proteins, Signal Transducing; D000076122:Disks Large Homolog 4 Protein; D015696:Gene Products, tat; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D048688:MAP Kinase Kinase 7; D020930:MAP Kinase Kinase Kinases; D008565:Membrane Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D018092:Kainic Acid Receptors; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; D000097806:GluK2 Kainate Receptor; C501449:Dlg4 protein, rat; C110528:Mapk8ip1 protein, rat