SHP2 as a primordial epigenetic enzyme expunges histone H3 pTyr-54 to amend androgen receptor homeostasis

Surbhi Chouhan, Dhivya Sridaran, Cody Weimholt, Jingqin Luo, Tiandao Li, Myles C. Hodgson, Luana N. Santos, Samantha Sommer, Bin Fang, John M. Koomen, Markus Seeliger, Cheng-Kui Qu, Armelle Yart, Maria I. Kontaridis, Kiran Mahajan and Nupam P. Mahajan ()
Additional contact information
Surbhi Chouhan: Washington University in St Louis
Dhivya Sridaran: Washington University in St Louis
Cody Weimholt: Washington University in St Louis
Jingqin Luo: Washington University in St Louis
Tiandao Li: Washington University in St Louis
Myles C. Hodgson: Masonic Medical Research Institute
Luana N. Santos: Masonic Medical Research Institute
Samantha Sommer: Masonic Medical Research Institute
Bin Fang: SRB3
John M. Koomen: SRB3
Markus Seeliger: Stony Brook University Medical School, BST 7-120
Cheng-Kui Qu: Emory University School of Medicine
Armelle Yart: UMR 1301-Inserm 5070-CNRS EFS Univ. P. Sabatier
Maria I. Kontaridis: Masonic Medical Research Institute
Kiran Mahajan: Washington University in St Louis
Nupam P. Mahajan: Washington University in St Louis

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Mutations that decrease or increase the activity of the tyrosine phosphatase, SHP2 (encoded by PTPN11), promotes developmental disorders and several malignancies by varying phosphatase activity. We uncovered that SHP2 is a distinct class of an epigenetic enzyme; upon phosphorylation by the kinase ACK1/TNK2, pSHP2 was escorted by androgen receptor (AR) to chromatin, erasing hitherto unidentified pY54-H3 (phosphorylation of histones H3 at Tyr54) epigenetic marks to trigger a transcriptional program of AR. Noonan Syndrome with Multiple Lentigines (NSML) patients, SHP2 knock-in mice, and ACK1 knockout mice presented dramatic increase in pY54-H3, leading to loss of AR transcriptome. In contrast, prostate tumors with high pSHP2 and pACK1 activity exhibited progressive downregulation of pY54-H3 levels and higher AR expression that correlated with disease severity. Overall, pSHP2/pY54-H3 signaling acts as a sentinel of AR homeostasis, explaining not only growth retardation, genital abnormalities and infertility among NSML patients, but also significant AR upregulation in prostate cancer patients.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-49978-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49978-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-49978-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().