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Human prostatic acid phosphatase, an authentic tyrosine phosphatase, dephosphorylates ErbB-2 and regulates prostate

Tsai-Der Chuang1, Siu-Ju Chen, Fen-Fen Lin

  • 1Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.

The Journal of Biological Chemistry
|May 26, 2010
PubMed

Insights

Cellular prostatic acid phosphatase (cPAcP) dephosphorylates ErbB-2 at Tyr(1221/2), inhibiting prostate cancer cell growth. Reduced cPAcP expression promotes androgen-independent growth and tumorigenicity in advanced prostate cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Cellular prostatic acid phosphatase (cPAcP) is a tyrosine phosphatase implicated in regulating prostate cancer (PCa) cell growth.
  • Its role as a negative regulator is partly attributed to dephosphorylating ErbB-2, but direct interaction and specific phosphorylation sites remained unelucidated.

Purpose of the Study:

  • To investigate the direct interaction between cPAcP and ErbB-2.
  • To identify the specific dephosphorylation site(s) on ErbB-2 by cPAcP.
  • To elucidate the functional consequences of cPAcP-ErbB-2 interaction on PCa cell signaling and growth.

Main Methods:

  • Co-immunoprecipitation assays to demonstrate protein-protein interaction.
  • Western blotting to assess protein phosphorylation levels at specific tyrosine residues (e.g., ErbB-2 Tyr(1221/2), p52(Shc) Tyr(317)).
  • Gene expression manipulation using cDNA and short hairpin RNA (shRNA) to alter cPAcP levels in PCa cell lines (LNCaP, MDA PCa2b).
  • Cell proliferation assays, xenograft studies in animals to evaluate tumorigenicity.

Main Results:

  • Phosphorylation of ErbB-2 at Tyr(1221/2) positively correlated with PCa cell growth rates.
  • cPAcP was shown to reciprocally co-immunoprecipitate with ErbB-2.
  • Overexpression of wild-type cPAcP decreased ErbB-2 Tyr(1221/2) phosphorylation, p52(Shc) Tyr(317) phosphorylation, and cell growth.
  • Knockdown of cPAcP increased ErbB-2 Tyr(1221/2) phosphorylation, activated downstream signaling pathways (p52(Shc), ERK1/2, Akt, Src, STAT-3, STAT-5), and enhanced cell proliferation, PCNA, and cyclin D1 expression.
  • Reduced cPAcP expression led to androgen-independent growth and increased tumorigenicity in vivo.

Conclusions:

  • cPAcP directly interacts with and dephosphorylates ErbB-2, primarily at Tyr(1221/2), thereby inhibiting downstream signaling and reducing prostate cancer cell growth.
  • Decreased cPAcP expression is a critical event associated with the transition to androgen-independent proliferation and increased tumorigenicity in advanced, hormone-refractory prostate cancer.

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