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The Ron receptor tyrosine kinase activates c-Abl to promote cell proliferation through tyrosine phosphorylation of PCNA in breast cancer

Oncogene volume 33, pages 1429–1437 (2014)Cite this article

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Abstract

Multiple growth pathways lead to enhanced proliferation in malignant cells. However, how the core machinery of DNA replication is regulated by growth signaling remains largely unclear. The sliding clamp proliferating cell nuclear antigen (PCNA) is an indispensable component of the DNA machinery responsible for replicating the genome and maintaining genomic integrity. We previously reported that epidermal growth factor receptor (EGFR) triggered tyrosine 211 (Y211) phosphorylation of PCNA, which in turn stabilized PCNA on chromatin to promote cell proliferation. Here we show that the phosphorylation can also be catalyzed by the non-receptor tyrosine kinase c-Abl. We further demonstrate that, in the absence of EGFR, signaling to PCNA can be attained through the activation of the Ron receptor tyrosine kinase and the downstream non-receptor tyrosine kinase c-Abl. We show that Ron and c-Abl form a complex, and that activation of Ron by its ligand, hepatocyte growth factor-like protein (HGFL), stimulates c-Abl kinase activity, which in turn directly phosphorylates PCNA at Y211 and leads to an increased level of chromatin-associated PCNA. Correspondingly, HGFL-induced Ron activation resulted in Y211 phosphorylation of PCNA while silencing of c-Abl blocked this effect. We show that c-Abl and Y211 phosphorylation of PCNA is an important axis downstream of Ron, which is required for cell proliferation. Treatment with a specific peptide that inhibits Y211 phosphorylation of PCNA or with the c-Abl pharmacological inhibitor imatinib suppressed HGFL-induced cell proliferation. Our findings identify the pathway of Ron-c-Abl-PCNA as a mechanism of oncogene-induced cell proliferation, with potentially important implications for development of combination therapy of breast cancer.

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Acknowledgements

We thank Drs David Plas and Daniel Starczynowski for the help in discussion and reagents. We also like to thank Dr Belinda Peace and Glenn Doerman for assistance in editing the manuscript and preparing the graphics, and Jerylin Gray for technical assistance. This work was supported in part by the Susan G Komen Breast Cancer Research Award KG080540, the Department of Defense Prostate Cancer Research Program New Investigator Award PC073951, the Center for Clinical and Translational Science and Training (CCTST) of University of Cincinnati and Cincinnati Children’s Hospital, and the Elsa Pardee Foundation (S-CW), the VA Merit Award 1001BX000803 and R01 CA125379 (SEW), and R01 CA116784 (RP). This project was also supported in part by PHS Grant P30 DK078392.

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Authors and Affiliations

  1. Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    H Zhao, M-S Chen, Y-H Lo, S E Waltz, P-C Ho, J Vasiliauskas, Y-L Wang & S-C Wang

  2. Cincinnati Veterans Affairs Medical Center, Cincinnati, OH, USA

    S E Waltz

  3. Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, OH, USA

    J Wang

  4. Department of Molecular and Biomedical Pharmacology, University of Kentucky School of Medicine, Lexington, KY, USA

    R Plattner

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Zhao, H., Chen, MS., Lo, YH. et al. The Ron receptor tyrosine kinase activates c-Abl to promote cell proliferation through tyrosine phosphorylation of PCNA in breast cancer. Oncogene 33, 1429–1437 (2014). https://doi.org/10.1038/onc.2013.84

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