Dynamic subcellular localization and transcription activity of the SRF cofactor MKL2 in the striatum are regulated by MAPK

AbstractDopamine type 1 receptor (D1R) signaling activates protein kinase A (PKA), which then activates mitogen ‐activated protein kinase (MAPK) through Rap1, in striatal medium spiny neurons (MSNs). MAPK plays a pivotal role in reward‐related behavior through the activation of certain transcription factors. How D1R signaling regulates behavior through transcription factors remains largely unknown. CREB‐ binding protein (CBP) promotes transcription through hundreds of different transcription factors and is also important for reward‐related behavior. To identify transcription factors regulated by dopamine signaling in MSNs, we performed a phosphoproteomic analysis using affinity beads coated with C BP. We obtained approximately 40 novel candidate proteins in the striatum of the C57BL/6 mouse brain after cocaine administration. Among them, the megakaryoblastic leukemia‐2 (MKL2) protein, a transcriptional coactivator of serum response factor (SRF), was our focus. We found that the interaction between CBP and MKL2 was increased by cocaine administration. Additionally, MKL2, CBP and SRF formed a ternary complexin vivo. The C ‐terminal domain of MKL2 interacted with CBP‐KIX and was phosphorylated by MAPK in COS7 cells. The activation of PKA‐MAPK signaling induced the nuclear localization of MKL2 and increased SRF‐dependent transcriptional activity in neurons. These results demonstrate that dopamine signaling regu lates the interaction of MKL2 with CBP in a phospho...
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: ORIGINAL ARTICLE Source Type: research