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Differential phosphorylation of calreticulin affects AT1 receptor mRNA stability in VSMC

Cornelius F H Mueller1, Kerstin Wassmann, Anja Berger

  • 1Medizinische Klinik und Poliklinik II, Innere Medizin, Universitätsklinikum Bonn, Sigmund Freud Strasse 25, 53105 Bonn, Germany. cornelius.mueller@ukb.uni-bonn.de

Biochemical and Biophysical Research Communications
|April 17, 2008
PubMed

Insights

Calreticulin binds to AT1 receptor mRNA, regulating its stability. Src kinase and specific phosphorylation patterns of calreticulin are crucial for this process, impacting hypertension and atherosclerosis development.

Area of Science:

  • Molecular Biology
  • Cardiovascular Research

Background:

  • The angiotensin II type 1 (AT1) receptor is crucial in hypertension and atherosclerosis.
  • AT1 receptor expression is controlled post-transcriptionally by mRNA-binding proteins that destabilize AT1 receptor mRNA.

Purpose of the Study:

  • To investigate the role of calreticulin as an mRNA-binding protein for the AT1 receptor mRNA.
  • To identify the signaling pathways regulating calreticulin's interaction with AT1 receptor mRNA and its impact on mRNA stability.

Main Methods:

  • Identification of calreticulin as an AT1 receptor mRNA-binding protein.
  • Crosslinking experiments to identify src kinase as the enzyme responsible for calreticulin phosphorylation.
  • Overexpression studies of src sense and antisense DNA in vascular smooth muscle cells (VSMC).
  • Analysis of calreticulin phosphorylation (tyrosine and serine) in VSMC stimulated with AngII.
  • Assessment of AT1 receptor mRNA stability using pharmacological inhibitors.

Main Results:

  • Calreticulin binds to the 3'untranslated region of AT1 receptor mRNA.
  • Src kinase phosphorylates calreticulin, which is essential for its binding to AT1 receptor mRNA.
  • Overexpression of src sense DNA destabilized AT1 receptor mRNA, while antisense stabilized it in VSMC.
  • AngII stimulation of VSMC enhanced tyrosine phosphorylation and reduced serine phosphorylation of calreticulin.
  • Pharmacological inhibition of serine dephosphorylation or tyrosine phosphorylation affected AT1 receptor mRNA stability.

Conclusions:

  • Calreticulin is a key regulator of AT1 receptor mRNA stability.
  • Src kinase-mediated phosphorylation of calreticulin is critical for AT1 receptor mRNA binding and destabilization.
  • AngII-induced changes in calreticulin phosphorylation (increased tyrosine, decreased serine) are essential for AT1 receptor mRNA stability.

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