Tyrosine phosphorylation controls PCNA function through protein stability.
The proliferating cell nuclear antigen (PCNA) is an essential protein for DNA replication and damage repair. How its function is controlled remains an important question. Here, we show that the chromatin-bound PCNA protein is phosphorylated on Tyr 211, which is required for maintaining its function on chromatin and is dependent on the tyrosine kinase activity of EGF receptor (EGFR) in the nucleus. Phosphorylation on Tyr 211 by EGFR stabilizes chromatin-bound PCNA protein and associated functions. Consistently, increased PCNA Tyr 211 phosphorylation coincides with pronounced cell proliferation, and is better correlated with poor survival of breast cancer patients, as well as nuclear EGFR in tumours, than is the total PCNA level. These results identify a novel nuclear mechanism linking tyrosine kinase receptor function with the regulation of the PCNA sliding clamp.
Wang
Shao-Chun
SC
Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Nakajima
Yusuke
Y
Yu
Yung-Luen
YL
Xia
Weiya
W
Chen
Chun-Te
CT
Yang
Cheng-Chieh
CC
McIntush
Eric W
EW
Li
Long-Yuan
LY
Hawke
David H
DH
Kobayashi
Ryuji
R
Hung
Mien-Chie
MC
D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002843:Chromatin / Q000378:metabolism; D004260:DNA Repair; D004261:DNA Replication; D066246:ErbB Receptors / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism*; D018809:Proliferating Cell Nuclear Antigen / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D013816:Thermodynamics
D002843:Chromatin; D018809:Proliferating Cell Nuclear Antigen; D019000:Phosphotyrosine; D066246:ErbB Receptors