SHARPIN-mediated regulation of protein arginine methyltransferase 5 controls melanoma growth

Hironari Tamiya; Hyungsoo Kim; Oleksiy Klymenko; Heejung Kim; Yongmei Feng; Tongwu Zhang; Ji Yun Han; Ayako Murao; Scott J. Snipas; Lucia Jilaveanu; Kevin Brown; Harriet Kluger; Hao Zhang; Kazuhiro Iwai; Zeev A. Ronai

doi:10.1172/JCI95410

SHARPIN-mediated regulation of protein arginine methyltransferase 5 controls melanoma growth

Hironari Tamiya, Hyungsoo Kim, Oleksiy Klymenko, Heejung Kim, Yongmei Feng, Tongwu Zhang, Ji Yun Han, Ayako Murao, Scott J. Snipas, Lucia Jilaveanu, Kevin Brown, Harriet Kluger, Hao Zhang, Kazuhiro Iwai, Zeev A. Ronai

Research output: Contribution to journal › Article › peer-review

34 Scopus citations

Abstract

SHARPIN, an adaptor for the linear ubiquitin chain assembly complex (LUBAC), plays important roles in NF-κB signaling and inflammation. Here, we have demonstrated a LUBAC-independent role for SHARPIN in regulating melanoma growth. We observed that SHARPIN interacted with PRMT5, a type II protein arginine methyltransferase, and increased its multiprotein complex and methyltransferase activity. Activated PRMT5 controlled the expression of the transcription factors SOX10 and MITF by SHARPIN-dependent arginine dimethylation and inhibition of the transcriptional corepressor SKI. Activation of PRMT5 by SHARPIN counteracted PRMT5 inhibition by methylthioadenosine, a substrate of methylthioadenosine phosphorylase, which is codeleted with cyclin-dependent kinase inhibitor 2A (CDKN2A) in approximately 15% of human cancers. Collectively, we identified a LUBAC-independent role for SHARPIN in enhancing PRMT5 activity that contributes to melanomagenesis through the SKI/SOX10 regulatory axis.

Original language	English
Pages (from-to)	517-530
Number of pages	14
Journal	Journal of Clinical Investigation
Volume	128
Issue number	1
DOIs	https://doi.org/10.1172/JCI95410
State	Published - 2 Jan 2018
Externally published	Yes

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@article{f031ff53f41d4072b89b704860f5e8a3,

title = "SHARPIN-mediated regulation of protein arginine methyltransferase 5 controls melanoma growth",

abstract = "SHARPIN, an adaptor for the linear ubiquitin chain assembly complex (LUBAC), plays important roles in NF-κB signaling and inflammation. Here, we have demonstrated a LUBAC-independent role for SHARPIN in regulating melanoma growth. We observed that SHARPIN interacted with PRMT5, a type II protein arginine methyltransferase, and increased its multiprotein complex and methyltransferase activity. Activated PRMT5 controlled the expression of the transcription factors SOX10 and MITF by SHARPIN-dependent arginine dimethylation and inhibition of the transcriptional corepressor SKI. Activation of PRMT5 by SHARPIN counteracted PRMT5 inhibition by methylthioadenosine, a substrate of methylthioadenosine phosphorylase, which is codeleted with cyclin-dependent kinase inhibitor 2A (CDKN2A) in approximately 15% of human cancers. Collectively, we identified a LUBAC-independent role for SHARPIN in enhancing PRMT5 activity that contributes to melanomagenesis through the SKI/SOX10 regulatory axis.",

author = "Hironari Tamiya and Hyungsoo Kim and Oleksiy Klymenko and Heejung Kim and Yongmei Feng and Tongwu Zhang and Han, {Ji Yun} and Ayako Murao and Snipas, {Scott J.} and Lucia Jilaveanu and Kevin Brown and Harriet Kluger and Hao Zhang and Kazuhiro Iwai and Ronai, {Zeev A.}",

note = "Funding Information: We thank Keiji Miyazawa (University of Yamanashi) for providing expression vectors, and members of the Ronai lab for discussions. This work was supported by grants from the NCI (R21CA198468 to HK; R35CA197465 to ZAR) and the Shantou University-Tech-nion Research Program (to ZAR). Funding Information: We thank Keiji Miyazawa (University of Yamanashi) for providing expression vectors, and members of the Ronai lab for discussions. This work was supported by grants from the NCI (R21CA198468 to HK; R35CA197465 to ZAR) and the Shantou University-Technion Research Program (to ZAR).",

year = "2018",

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day = "2",

doi = "10.1172/JCI95410",

language = "English",

volume = "128",

pages = "517--530",

journal = "Journal of Clinical Investigation",

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T1 - SHARPIN-mediated regulation of protein arginine methyltransferase 5 controls melanoma growth

AU - Tamiya, Hironari

AU - Kim, Hyungsoo

AU - Klymenko, Oleksiy

AU - Kim, Heejung

AU - Feng, Yongmei

AU - Zhang, Tongwu

AU - Han, Ji Yun

AU - Murao, Ayako

AU - Snipas, Scott J.

AU - Jilaveanu, Lucia

AU - Brown, Kevin

AU - Kluger, Harriet

AU - Zhang, Hao

AU - Iwai, Kazuhiro

AU - Ronai, Zeev A.

N1 - Funding Information: We thank Keiji Miyazawa (University of Yamanashi) for providing expression vectors, and members of the Ronai lab for discussions. This work was supported by grants from the NCI (R21CA198468 to HK; R35CA197465 to ZAR) and the Shantou University-Tech-nion Research Program (to ZAR). Funding Information: We thank Keiji Miyazawa (University of Yamanashi) for providing expression vectors, and members of the Ronai lab for discussions. This work was supported by grants from the NCI (R21CA198468 to HK; R35CA197465 to ZAR) and the Shantou University-Technion Research Program (to ZAR).

PY - 2018/1/2

Y1 - 2018/1/2

N2 - SHARPIN, an adaptor for the linear ubiquitin chain assembly complex (LUBAC), plays important roles in NF-κB signaling and inflammation. Here, we have demonstrated a LUBAC-independent role for SHARPIN in regulating melanoma growth. We observed that SHARPIN interacted with PRMT5, a type II protein arginine methyltransferase, and increased its multiprotein complex and methyltransferase activity. Activated PRMT5 controlled the expression of the transcription factors SOX10 and MITF by SHARPIN-dependent arginine dimethylation and inhibition of the transcriptional corepressor SKI. Activation of PRMT5 by SHARPIN counteracted PRMT5 inhibition by methylthioadenosine, a substrate of methylthioadenosine phosphorylase, which is codeleted with cyclin-dependent kinase inhibitor 2A (CDKN2A) in approximately 15% of human cancers. Collectively, we identified a LUBAC-independent role for SHARPIN in enhancing PRMT5 activity that contributes to melanomagenesis through the SKI/SOX10 regulatory axis.

AB - SHARPIN, an adaptor for the linear ubiquitin chain assembly complex (LUBAC), plays important roles in NF-κB signaling and inflammation. Here, we have demonstrated a LUBAC-independent role for SHARPIN in regulating melanoma growth. We observed that SHARPIN interacted with PRMT5, a type II protein arginine methyltransferase, and increased its multiprotein complex and methyltransferase activity. Activated PRMT5 controlled the expression of the transcription factors SOX10 and MITF by SHARPIN-dependent arginine dimethylation and inhibition of the transcriptional corepressor SKI. Activation of PRMT5 by SHARPIN counteracted PRMT5 inhibition by methylthioadenosine, a substrate of methylthioadenosine phosphorylase, which is codeleted with cyclin-dependent kinase inhibitor 2A (CDKN2A) in approximately 15% of human cancers. Collectively, we identified a LUBAC-independent role for SHARPIN in enhancing PRMT5 activity that contributes to melanomagenesis through the SKI/SOX10 regulatory axis.

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DO - 10.1172/JCI95410

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SN - 0021-9738

VL - 128

SP - 517

EP - 530

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 1

ER -

SHARPIN-mediated regulation of protein arginine methyltransferase 5 controls melanoma growth

Abstract

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