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Site-selective regulation of platelet-derived growth factor beta receptor tyrosine phosphorylation by T-cell protein

Camilla Persson1, Catrine Sävenhed, Annie Bourdeau

  • 1Ludwig Institute for Cancer Research, Uppsala Branch, Biomedical Center, S-751 24 Uppsala, Sweden.

Molecular and Cellular Biology
|February 18, 2004
PubMed

Insights

T-cell PTP (TC-PTP) negatively regulates the PDGF beta receptor. Loss of TC-PTP leads to hyperphosphorylation of the PDGF beta receptor, enhancing cell migration.

Area of Science:

  • Cellular signaling pathways
  • Receptor tyrosine kinase regulation
  • Protein tyrosine phosphatases

Background:

  • Platelet-derived growth factor (PDGF) beta receptor is crucial for cell growth and migration.
  • Protein tyrosine phosphatases (PTPs) are known negative regulators of tyrosine kinase receptors.
  • The specific role of T-cell PTP (TC-PTP) in PDGF beta receptor signaling was previously unclear.

Purpose of the Study:

  • To investigate whether TC-PTP negatively regulates the PDGF beta receptor.
  • To determine the impact of TC-PTP deficiency on PDGF beta receptor phosphorylation and signaling.
  • To explore the site-selectivity of PTPs on the PDGF beta receptor.

Main Methods:

  • Comparison of PDGF beta receptor tyrosine phosphorylation in wild-type and TC-PTP knockout (ko) mouse embryos and fibroblasts.
  • Assessment of ligand-induced receptor phosphorylation and phospholipase Cgamma1 activity.
  • Analysis of PDGF beta receptor phosphorylation at specific autophosphorylation sites using site-specific antibodies.
  • Evaluation of PDGF-induced cell migration in PTP-deficient cells.

Main Results:

  • PDGF beta receptors were significantly hyperphosphorylated in TC-PTP ko embryos and fibroblasts.
  • Re-expression of TC-PTP partially reversed the hyperphosphorylation.
  • The Y1021 phosphorylation site, crucial for chemotaxis, showed the most significant increase.
  • TC-PTP deficiency led to increased phospholipase Cgamma1 activity and migratory hyperresponsiveness to PDGF.
  • PTP-1B knockout also resulted in higher PDGF beta receptor phosphorylation, but with a different site distribution and without increased PDGF-induced migration.

Conclusions:

  • TC-PTP is identified as a novel negative regulator of PDGF beta receptor signaling.
  • TC-PTP deficiency enhances PDGF beta receptor phosphorylation, leading to increased cell migration.
  • These findings highlight the site-selective action of PTPs on tyrosine kinase receptors and their role in cellular responses.

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