Mixed lineage kinase 2 enhances trans-repression of Alien and nuclear receptors.
Alien was previously identified as a corepressor for the thyroid hormone receptor (TR) and DAX-1 which belong both to the superfamily of nuclear receptors. Here, we isolated the mixed lineage kinase 2 (MLK2) as an interacting partner for the corepressor Alien using a yeast two hybrid screen. MLK2 is an upstream activator of JNKs and activation of MLK2-mediated signaling cascades play roles in neurodegenerative and apoptotic mechanisms in the central nervous system. MLK2 has been shown to be localized both in the cytoplasm and cell nucleus. We confirmed the Alien-MLK2 interaction using GST pull-down experiments and also show that MLK2 is able to phosphorylate Alien in immune-kinase assays. Functional analyses revealed that Alien, DAX-1 and thyroid hormone receptor mediated transcriptional silencing is strongly enhanced in the presence of active MLK2. Since MAP kinase signaling pathways are important mediators of cellular responses to a wide variety of stimuli, our data suggest that signaling pathways not only regulate transactivation but also enhancement of transcriptional silencing. This novel cross-talk may represent a link between MLK2-mediated signaling and transcriptional repression of target genes during neuronal differentiation processes.
Eckey
Maren
M
Genetic Institute, Justus-Liebig-University, Heinrich-Buff-Ring 58-62, D-35392 Giessen, Germany.
Tenbaum
Stephan P
SP
Muñoz
Alberto
A
Baniahmad
Aria
A
D000075686:COP9 Signalosome Complex; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins / Q000502:physiology; D020868:Gene Silencing; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding; D020239:Receptor Cross-Talk; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000502:physiology; D011988:Receptors, Thyroid Hormone / Q000502:physiology; D012097:Repressor Proteins / Q000378:metabolism* / Q000502:physiology*; D015398:Signal Transduction
C402762:COPS2 protein, human; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; C539965:NR0B1 protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D012097:Repressor Proteins; D020930:MAP Kinase Kinase Kinases; D000075686:COP9 Signalosome Complex