TY - JOUR
T1 - Dynamic subcellular localization and transcription activity of the SRF cofactor MKL2 in the striatum are regulated by MAPK
AU - Ariza, Anthony
AU - Funahashi, Yasuhiro
AU - Kozawa, Sachi
AU - Omar Faruk, Md
AU - Nagai, Taku
AU - Amano, Mutsuki
AU - Kaibuchi, Kozo
N1 - Funding Information:
The authors thank T. Nishioka, Y. Yamahashi, and K. Kuroda for their skilled assistance; other Kaibuchi lab members for their helpful discussion; and T. Ishii for secretarial assistance. The authors also thank K. Taki (Division for Research Engineering, Nagoya University Graduate School of Medicine) for help with MS data acquisition; N. Hamada and Y. Nakamura (Radioisotope Center Medical Branch, Nagoya University Graduate School of Medicine) for technical assistance; and the Division of Experimental Animals at Nagoya University Graduate School of Medicine for assistance with animal care. This work was supported by the following funding sources: ‘Bioinformatics for Brain Sciences' carried out under the SRPBS from MEXT and AMED; AMED under grant number JP20dm0207075; JSPS/MEXT KAKENHI grant numbers JP16K18393, JP17H01380, JP17K07383, JP18K14849, JP19H05209; the Uehara Memorial Foundation; and the Takeda Science Foundation.
Funding Information:
The authors thank T. Nishioka, Y. Yamahashi, and K. Kuroda for their skilled assistance; other Kaibuchi lab members for their helpful discussion; and T. Ishii for secretarial assistance. The authors also thank K. Taki (Division for Research Engineering, Nagoya University Graduate School of Medicine) for help with MS data acquisition; N. Hamada and Y. Nakamura (Radioisotope Center Medical Branch, Nagoya University Graduate School of Medicine) for technical assistance; and the Division of Experimental Animals at Nagoya University Graduate School of Medicine for assistance with animal care. This work was supported by the following funding sources: ‘Bioinformatics for Brain Sciences' carried out under the SRPBS from MEXT and AMED; AMED under grant number JP20dm0207075; JSPS/MEXT KAKENHI grant numbers JP16K18393, JP17H01380, JP17K07383, JP18K14849, JP19H05209; the Uehara Memorial Foundation; and the Takeda Science Foundation.
Publisher Copyright:
© 2021 International Society for Neurochemistry
PY - 2021/6
Y1 - 2021/6
N2 - 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. (Figure presented.). Cover Image for this issue: https://doi.org/10.1111/jnc.15067.
AB - 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. (Figure presented.). Cover Image for this issue: https://doi.org/10.1111/jnc.15067.
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U2 - 10.1111/jnc.15303
DO - 10.1111/jnc.15303
M3 - Article
C2 - 33449379
AN - SCOPUS:85100188572
VL - 157
SP - 1774
EP - 1788
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
SN - 0022-3042
IS - 6
ER -