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Regulation of cytosolic phospholipase A2 activity in macrophages stimulated with receptor-recognized forms of alpha 2-macroglobulin: role in mitogenesis and cell proliferation.

Publication ,  Journal Article
Misra, UK; Pizzo, SV
Published in: J Biol Chem
February 8, 2002

Macrophages exposed to receptor-recognized forms of alpha(2)-macroglobulin (alpha(2)M*) demonstrate increased DNA synthesis and cell division. In the current study, we have probed the role of cytosolic phospholipase A(2) (cPLA(2)) activity in the cellular response to alpha(2)M*. Ligation of the alpha(2)M* signaling receptor by alpha(2)M*, or its receptor binding fragment, increased cPLA(2) activity 2-3-fold in a concentration and time-dependent manner. This activation required a pertussis toxin-insensitive G protein. Cellular binding of alpha(2)M* also induced transient translocation of cPLA(2) activity to nuclei and membrane fractions. Inhibition of protein kinase C activity or chelation of Ca(2+) inhibited alpha(2)M*-induced increased cPLA(2) activity. Binding of alpha(2)M* to macrophages, moreover, increased phosphorylation of MEK 1/2, ERK 1/2, p38 MAPK, and JNK. Incubation of macrophages with inhibitors of MEK 1/2 or p38 MAPK before stimulation with alpha(2)M* profoundly decreased phosphorylation of MAPKs, blocking cPLA(2) activation. alpha(2)M*-induced increase in [(3)H]thymidine uptake and cell proliferation was completely abolished if activation of cPLA(2) was prevented. The response of macrophages to alpha(2)M* requires transcription factors nuclear factor kappaB, and cAMP-responsive element-binding protein as well as expression of the proto-oncogenes c-fos and c-myc. These studies indicate that the activation of cPLA(2) plays a crucial role in alpha(2)M*-induced mitogenesis and cell proliferation.

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Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

February 8, 2002

Volume

277

Issue

6

Start / End Page

4069 / 4078

Location

United States

Related Subject Headings

  • alpha-Macroglobulins
  • Phosphorylation
  • Phospholipases A2
  • Phospholipases A
  • NF-kappa B
  • Mitosis
  • Mitogen-Activated Protein Kinases
  • Mice, Inbred C57BL
  • Mice
  • Macrophages, Peritoneal
 

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

February 8, 2002

Volume

277

Issue

6

Start / End Page

4069 / 4078

Location

United States

Related Subject Headings

  • alpha-Macroglobulins
  • Phosphorylation
  • Phospholipases A2
  • Phospholipases A
  • NF-kappa B
  • Mitosis
  • Mitogen-Activated Protein Kinases
  • Mice, Inbred C57BL
  • Mice
  • Macrophages, Peritoneal