Differential molecular assemblies underlie the dual function of Axin in modulating the WNT and JNK pathways.
Axin is a multidomain scaffold protein that exerts a dual function in the Wnt signaling and MEKK1/JNK pathways. This raises a critical question as to whether Axin-based differential molecular assemblies exist and how these may act to coordinate the two separate pathways. Here we show that both wild-type glycogen synthase kinase-3 beta (GSK-3 beta) and kinase-dead GSK-3 beta-Y216F (capable of binding to Axin), but not GSK-3 beta-K85M (incapable of binding to Axin in mammalian cells), prevented MEKK1 binding to the Axin complex, thereby inhibiting JNK activation. We further show that casein kinase I epsilon also inhibited Axin-mediated JNK activation by competing against MEKK1 binding. In contrast, beta-catenin and adenomatous polyposis coli binding did not affect MEKK1 binding to the same Axin complex. This suggests that even when Axin is "switched" to activate the JNK pathway, it is still capable of sequestering free beta-catenin, which is a critical aspect for cellular homeostasis. Our results clearly demonstrate that differential molecular assemblies underlie the duality of Axin functions in the negative regulation of Wnt signaling and activation of the JNK MAPK pathway.
Zhang
Y
Y
Regulatory Biology Laboratory, Institute of Molecular and Cell Biology, Singapore 117609, Republic of Singapore.
Qiu
W J
WJ
Liu
D X
DX
Neo
S Y
SY
He
X
X
Lin
S C
SC
D060466:Axin Protein; D001483:Base Sequence; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D017931:DNA Primers; D015536:Down-Regulation; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011506:Proteins / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012097:Repressor Proteins; D015398:Signal Transduction / Q000502:physiology; D051153:Wnt Proteins; D029961:Zebrafish Proteins
D060466:Axin Protein; D017931:DNA Primers; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3