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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
07:41

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The role of cAMP-dependent signaling in receptor-recognized forms of alpha 2-macroglobulin-induced cellular

Uma Kant Misra1, Gamal Akabani, Salvatore Vincent Pizzo

  • 1Department of Pathology and Department of Radiology, Duke University Medical Center, Durham, North Carolina 27710, USA.

The Journal of Biological Chemistry
|July 13, 2002
PubMed

Insights

Alpha-2-macroglobulin (α(2)M*) binding to receptors activates signaling pathways, increasing cAMP and activating cAMP-response element-binding protein (CREB). This CREB activation is crucial for α(2)M*-induced macrophage proliferation.

Area of Science:

  • Cellular biology
  • Molecular signaling
  • Immunology

Background:

  • Alpha-2-macroglobulin (α(2)M*) binding to its receptors initiates signaling cascades.
  • α(2)M* has been shown to promote cell proliferation and elevate cAMP levels in macrophages.

Purpose of the Study:

  • To investigate the role of cAMP-response element-binding protein (CREB) in α(2)M*-mediated signaling.
  • To identify the specific signaling pathways involved in α(2)M*-induced CREB activation and subsequent macrophage proliferation.

Main Methods:

  • Stimulation of murine peritoneal macrophages with α(2)M*.
  • Measurement of CREB phosphorylation and expression.
  • Inhibition of various kinase pathways.
  • Gene silencing of CREB using double-stranded RNA.

Main Results:

  • α(2)M* stimulation led to a significant increase in CREB levels and phosphorylation at Ser(133).
  • Multiple signaling pathways, including PI3K and p21(ras)-dependent pathways, were implicated in α(2)M*-induced CREB activation.
  • Silencing CREB expression blocked α(2)M*-induced macrophage proliferation.

Conclusions:

  • cAMP-dependent signaling and other cascades are essential for α(2)M*-induced macrophage proliferation.
  • CREB activation is a critical downstream event in the α(2)M* signaling pathway that drives cell division.

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