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 p52(Shc) 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 p52(Shc) 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, p52(Shc) was hyperphosphorylated at Tyr317 (Y317). Conversely, p52(Shc) 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 p52(Shc) 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 p52(Shc) and abolishes androgen-stimulated proliferation, but not EGF-stimulated proliferation. Thus, Y317 of p52(Shc) serves as an important regulatory site that allows tyrosine phosphorylation pathways to moderate androgen sensitivity in human prostate cancer cells.