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PTPα-mediated Src activation by EGF in human breast cancer cells

Jiamin Wang1, Lili Yu, Xinmin Zheng

  • 1Department of Biochemistry and Molecular Cell Biology, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China.

Acta Biochimica Et Biophysica Sinica
|March 28, 2013
PubMed

Insights

Epidermal growth factor (EGF) activates Src in breast cancer cells via protein tyrosine phosphatase alpha (PTPα). This PTPα activation, mediated by PKCδ, is crucial for cancer cell colony formation and represents a potential therapeutic target.

Area of Science:

  • Cellular signaling pathways
  • Cancer biology
  • Enzymology

Background:

  • Protein tyrosine phosphatase alpha (PTPα) dephosphorylates Tyr527/530 on Src, activating it.
  • PTPα catalytic activity is regulated by phosphorylation at Ser180/Ser204 and dissociation from Grb2.
  • Dysregulation of PTPα and Src signaling is implicated in breast cancer progression.

Purpose of the Study:

  • To investigate the role of PTPα in epidermal growth factor receptor (EGFR) signaling-mediated Src activation in breast cancer cells.
  • To elucidate the regulatory mechanisms of PTPα activity by EGF stimulation.
  • To assess the therapeutic potential of targeting PTPα in breast cancer.

Main Methods:

  • Utilized BT-20 and SKBR3 breast cancer cell lines.
  • Stimulated cells with epidermal growth factor (EGF).
  • Employed protein kinase C delta (PKCδ) inhibitor (rottlerin), siRNA knockdown of PKCδ, PTPα mutants (PTPαS180A/S204A), and PTPα siRNA.
  • Assessed PTPα-Grb2 association, PTPα catalytic activity, Src activation, and colony formation.

Main Results:

  • EGF stimulation enhanced PTPα's ability to activate Src by dephosphorylating Tyr530.
  • EGF transiently decreased PTPα-Grb2 association and increased PTPα catalytic activity via Ser180/Ser204 phosphorylation.
  • PKCδ inhibition or knockdown, or PTPαS180A/S204A mutant overexpression blocked EGF-induced PTPα activation.
  • PTPα siRNA inhibited EGF-mediated Src activation and colony formation in cancer cells.

Conclusions:

  • PTPα acts as a crucial link between EGFR signaling and Src activation in breast cancer cells.
  • EGF-induced PTPα activation is regulated by PKCδ-mediated phosphorylation and Grb2 dissociation.
  • Targeting PTPα may offer a novel therapeutic strategy for breast cancer treatment.

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