p85alpha subunit of class IA PI-3 kinase is crucial for macrophage growth and migration.
Macrophages play an essential role in defending against invading pathogens by migrating to the sites of infection, removing apoptotic cells, and secreting inflammatory cytokines. The molecular mechanisms whereby macrophages regulate these processes are poorly understood. Using bone marrow-derived macrophages (BMMs) deficient in the expression of p85alpha-subunit of class IA phosphatidylinositol 3 (PI-3) kinase, we demonstrate 50% reduction in proliferation in response to macrophage-colony-stimulating factor (M-CSF) as well as granulocyte macrophage-colony-stimulating factor (GM-CSF) compared with wild-type controls. Furthermore, p85alpha-/- BMMs demonstrate a significant reduction in migration in a wound-healing assay compared with wild-type controls. The reduction in migration due to p85alpha deficiency in BMMs is associated with reduced adhesion and directed migration on fibronectin and vascular cell adhesion molecule-1. In addition, deficiency of p85alpha in BMMs also results in defective phagocytosis of sheep red blood cells. Biochemically, loss of p85alpha in BMMs results in reduced activation of Akt and Rac, but not Erk (extracellular signal-related kinase) mitogen-activated protein (MAP) kinase. Taken together, our results provide genetic evidence for the importance of p85alpha in regulating both actin- and growth-based functions in macrophages, and provide a potential therapeutic target for the treatment of diseases involving macrophages, including inflammation.
Munugalavadla
Veerendra
V
Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Borneo
Jovencio
J
Ingram
David A
DA
Kapur
Reuben
R
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000201:enzymology; D002448:Cell Adhesion / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D004912:Erythrocytes; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D008264:Macrophages / Q000166:cytology* / Q000201:enzymology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010587:Phagocytosis / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012756:Sheep; D020744:rac GTP-Binding Proteins / Q000378:metabolism
D048049:Extracellular Signal-Regulated MAP Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D020744:rac GTP-Binding Proteins