Dynamic subcellular localization and transcription activity of the SRF cofactor MKL2 in the striatum are regulated by MAPK. Issue 6 (3rd February 2021)

• Record Type: Journal Article
• Authors: Ariza, Anthony; Funahashi, Yasuhiro; Kozawa, Sachi; Omar Faruk, Md.; Nagai, Taku; Amano, Mutsuki; Kaibuchi, Kozo
• Is Part Of: Journal of neurochemistry. Volume 157:Issue 6(2021)
• Page Start: 1774
• Page End: 1788
• Publication Date: 2021-02-03
• Subjects: Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.15303
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: Dopamine 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 CBP. 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 complex in 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 regulates the interaction of MKL2 with CBP in a phosphorylation‐dependent manner and thereby controls SRF‐dependent gene expression. Cover Image for this issue: https://doi.org/10.1111/jnc.15067 . Abstract : We proposed the following signaling cascade downstream D1R in the striatum: Activation of D1R activates PKA, which then activates MAPK through Rap1 in D1R‐MSNs. MAPK phosphorylates MKL2 and induces its nuclear localization. Once in the nucleus, MKL2 interacts with CBP in a phosphorylation‐dependent manner and controls the expression of reward‐related genes. We think our findings provide new insight for the potential treatment of drug addiction. Cover Image for this issue: https://doi.org/10.1111/jnc.15067 .