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PMID:17348686

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Citation

Zhang, QX, Pei, DS, Guan, QH, Sun, YF, Liu, XM and Zhang, GY (2007) Crosstalk between PSD-95 and JIP1-mediated signaling modules: the mechanism of MLK3 activation in cerebral ischemia. Biochemistry 46:4006-16

Abstract

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.

Links

PubMed Online version:10.1021/bi0615386

Keywords

Adaptor Proteins, Signal Transducing/physiology; Animals; Brain Ischemia/physiopathology; Dimerization; Gene Products, tat/pharmacology; Hippocampus/physiopathology; Intracellular Signaling Peptides and Proteins/physiology; JNK Mitogen-Activated Protein Kinases/physiology; MAP Kinase Kinase 7/physiology; MAP Kinase Kinase Kinases/physiology; Male; Membrane Proteins/physiology; Models, Biological; Oligodeoxyribonucleotides, Antisense/pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Kainic Acid/physiology; Reperfusion Injury/physiopathology; Signal Transduction/drug effects

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:MK08

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

RGD:70937

F

Seeded From UniProt

complete

RAT:MK09

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

RGD:70937

F

Seeded From UniProt

complete

RAT:MK09

involved_in

GO:0046328: regulation of JNK cascade

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:MP2K7

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

RGD:70937

F

Seeded From UniProt

complete

RAT:M3K11

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

RGD:70937

F

Seeded From UniProt

complete

RAT:JIP1

enables

GO:0031434: mitogen-activated protein kinase kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

RGD:1560043

F

Seeded From UniProt

complete

RAT:JIP1

enables

GO:0031435: mitogen-activated protein kinase kinase kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

RGD:1359261

F

Seeded From UniProt

complete

RAT:JIP1

enables

GO:0008432: JUN kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

RGD:628847

F

Seeded From UniProt

complete

RAT:JIP1

enables

GO:0008432: JUN kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

RGD:621506

F

Seeded From UniProt

complete

RAT:JIP1

enables

GO:0005078: MAP-kinase scaffold activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

See also

References

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