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Tyrosine-317 of p52Shc mediates androgen-stimulated proliferation signals in human prostate cancer cells

Oncogene volume 23, pages 3048–3058 (2004)Cite this article

Abstract

The involvement of tyrosine phosphorylation signaling pathways in steroid-induced cell proliferation has received much attention. However, the adaptor molecule that mediates this interaction remains to be identified. In this communication, we identify p52Shc as the mediator between tyrosine phosphorylation signaling and steroid signaling in steroid-responsive cell proliferation. Although the different LNCaP prostate cancer cells, C-33, C-51 and C-81, express similar levels of functional androgen receptor (AR), they exhibit different levels of androgen sensitivity. C-33 cell proliferation is highly responsive to the presence of androgens, whereas C-51 cell proliferation is comparatively less responsive to androgens. In contrast, C-81 cell proliferation is independent of androgens. In these cells, tyrosine phosphorylation levels of both p52Shc and ErbB-2 were greatest in C-81 cells, comparatively less in C-51 cells and weaker in C-33 cells. The levels and activity of protein tyrosine phosphatase, cellular prostatic acid phosphatase, decreased correspondingly in those cells. In both androgen-independent, rapidly growing C-81 and ErbB-2 cDNA-transfected C-33 cells, p52Shc was hyperphosphorylated at Tyr317 (Y317). Conversely, p52Shc tyrophosphorylation was decreased in prostatic acid phosphatase cDNA-transfected stable subclones of C-81 cells, which restore androgen-sensitive proliferation and leads to slow growth rates. In C-33 cells, androgen-stimulated cell proliferation correlated with tyrophosphorylation of ErbB-2 and increased phosphorylation of p52Shc at Y317, but not at Y239, differing from phosphorylation patterns associated with epidermal growth factor (EGF) stimulation. Furthermore, overexpression of a mutant of p52Shc, that is Y317F, blocks Y317 phosphorylation of endogenous p52Shc and abolishes androgen-stimulated proliferation, but not EGF-stimulated proliferation. Thus, Y317 of p52Shc serves as an important regulatory site that allows tyrosine phosphorylation pathways to moderate androgen sensitivity in human prostate cancer cells.

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Abbreviations

Ab:

antibody

AR:

androgen receptor

BPH:

benign prostatic hyperplasia

ECL:

enhanced chemiluminescence

EGF:

epidermal growth factor

FBS:

fetal bovine serum

IgG:

immunoglobulin G

MAPK:

microtubule-associated protein kinase or mitogen-activated protein kinase

PAcP:

prostatic acid phosphatase

cPAcP:

cellular PAcP

PNPP:

p-nitrophenyl phosphate

PTK:

protein tyrosine kinase

PTP:

protein tyrosine phosphatase

p-Tyr:

phosphotyrosine

RT–PCR:

reverse transcriptase–polymerase chain reaction

RPTK:

receptor protein tyrosine kinase

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Acknowledgements

We thank Dr Kodimangalam, S Ravichandran and Mr Scott Walk at the Beirne Carter Center for Immunology Research and Department of Microbiology (University of Virginia, Charlottesville, VA, USA) for their generous support in providing p52Shc plasmids. We thank Ms Fen-Fen Lin for her technical assistance in conducting some cell growth regulation, Ms Corrisa Moore for the preparation of Shc plasmids and Dr Richard G MacDonald for providing normal rabbit IgG. We also appreciate Drs Tzu-Ching Meng, Stanislav Zelivianski and Xiu-Qing Zhang for their helpful discussions, and Dr Marcia S Noble at Lombardi Cancer Center, Georgetown University Medical Center, for her editorial support. This study was supported in part by NIH Grant CA88184, Nebraska Department of Health and Human Services and Eppley Cancer Center LB595, National Kidney Foundation of Nebraska, and the Presidential Fellowship from the University of Nebraska.

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Author notes

  1. Ming-Shyue Lee

    Present address: Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC, 20057, USA

  2. Tsukasa Igawa

    Present address: Department of Urology, Nagasaki University School of Medicine, Sakamoto 1-7-1, Nagasaki, 852-8501, Japan

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 984525 Nebraska Medical Center, Omaha, 68198-4525, NE, USA

    Ming-Shyue Lee, Tsukasa Igawa & Ming-Fong Lin

  2. Section of Urologic Surgery, University of Nebraska Medical Center, Omaha, 68198, NE, USA

    Ming-Fong Lin

  3. Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, 68198, NE, USA

    Ming-Fong Lin

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  1. Ming-Shyue Lee
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Correspondence to Ming-Fong Lin.

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Lee, MS., Igawa, T. & Lin, MF. Tyrosine-317 of p52Shc mediates androgen-stimulated proliferation signals in human prostate cancer cells. Oncogene 23, 3048–3058 (2004). https://doi.org/10.1038/sj.onc.1207451

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