Arginine methylation of SHANK2 by PRMT7 promotes human breast cancer metastasis through activating endosomal FAK signalling
Abstract
Arginine methyltransferase PRMT7 is associated with human breast cancer metastasis. Endosomal FAK signalling is critical for cancer cell migration. Here we identified the pivotal roles of PRMT7 in promoting endosomal FAK signalling activation during breast cancer metastasis. PRMT7 exerted its functions through binding to scaffold protein SHANK2 and catalyzing di-methylation of SHANK2 at R240. SHANK2 R240 methylation exposed ANK domain by disrupting its SPN-ANK domain blockade, promoting in co-accumulation of dynamin2, talin, FAK, cortactin with SHANK2 on endosomes. In addition, SHANK2 R240 methylation activated endosomal FAK/cortactin signals in vitro and in vivo. Consistently, all the levels of PRMT7, methylated SHANK2, FAK Y397 phosphorylation and cortactin Y421 phosphorylation were correlated with aggressive clinical breast cancer tissues. These findings characterize the PRMT7-dependent SHANK2 methylation as a key player in mediating endosomal FAK signals activation, also point to the value of SHANK2 R240 methylation as a target for breast cancer metastasis.
Data availability
PDB accession number for SHANK2 structure analyse is pdb5G4X. Analysis of SHANK2 gene expression in human tissues using the Human Protein Atlas data.
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The crystal structure of the SHANK3 N-terminusProtein Data Bank, 5G4X.
Article and author information
Author details
Funding
National Natural Science Foundation of China (31870765)
- Baiqu Huang
National Natural Science Foundation of China (31571317)
- Jun Lu
National Natural Science Foundation of China (31570718)
- Baiqu Huang
National Natural Science Foundation of China (31771335)
- Yu Zhang
National Natural Science Foundation of China (31770825)
- Jun Lu
National Natural Science Foundation of China (21807098)
- Yibo Wang
Natural Science Foundation of Jilin Province (20180101232JC)
- Jun Lu
Natural Science Foundation of Jilin Province (20180101234JC)
- Yu Zhang
Natural Science Foundation of Jilin Province (20200404106YY)
- Yu Zhang
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Lynne-Marie Postovit, University of Alberta, Canada
Ethics
Animal experimentation: All animal works were conducted in accordance with the IACUC guidelines and with the protocol approved by the IACUC at the Northeast Normal University, reference assurance number AP2013011.
Human subjects: Human breast tumour specimens were obtained from the Second Hospital of Jilin University, China. All the breast cancer tissue samples were collected from 27 patients enrolled on pathology department of the Second Hospital of Jilin University. All the samples were diagnosed by the pathology department of the Second Hospital of Jilin University to determine the stage and subtype of the breast tumour. This experiment is an immunohistochemical study, no informed consent was needed due to the use of post-diagnostic left-over material. Ethical approval was obtained from the Ethics Review Committee of the Second Hospital of Jilin University (2019-107).
Version history
- Received: April 6, 2020
- Accepted: August 25, 2020
- Accepted Manuscript published: August 26, 2020 (version 1)
- Version of Record published: September 16, 2020 (version 2)
Copyright
© 2020, Liu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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