TY - JOUR
T1 - Tyrosine-317 of p52Shc mediates androgen-stimulated proliferation signals in human prostate cancer cells
AU - Lee, Ming Shyue
AU - Igawa, Tsukasa
AU - Lin, Ming Fong
N1 - Funding Information:
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.
PY - 2004/4/15
Y1 - 2004/4/15
N2 - 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 p52 Shc, 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.
AB - 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 p52 Shc, 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.
KW - Androgen sensitivity
KW - ErbB-2
KW - Human prostate cancer
KW - PAcP
KW - p52
UR - http://www.scopus.com/inward/record.url?scp=2442471671&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=2442471671&partnerID=8YFLogxK
U2 - 10.1038/sj.onc.1207451
DO - 10.1038/sj.onc.1207451
M3 - Article
C2 - 14990987
AN - SCOPUS:2442471671
SN - 0950-9232
VL - 23
SP - 3048
EP - 3058
JO - Oncogene
JF - Oncogene
IS - 17
ER -