Phosphatidylinositol 3-kinase-dependent mitogen-activated protein/extracellular signal-regulated kinase kinase 1/2 and NF-kappa B signaling pathways are required for B cell antigen receptor-mediated cyclin D2 induction in mature B cells

J Immunol. 2004 Mar 1;172(5):2753-62. doi: 10.4049/jimmunol.172.5.2753.

Abstract

Phosphatidylinositol 3-kinase (PI-3K) has been linked to promitogenic responses in splenic B cells following B cell Ag receptor (BCR) cross-linking; however identification of the signaling intermediates that link PI-3K activity to the cell cycle remains incomplete. We show that cyclin D2 induction is blocked by the PI-3K inhibitors wortmannin and LY294002, which coincides with impaired BCR-mediated mitogen-activated protein/extracellular signal-related kinase kinase (MEK)1/2 and p42/44ERK phosphorylation on activation residues. Cyclin D2 induction is virtually absent in B lymphocytes from mice deficient in the class I(A) PI-3K p85alpha regulatory subunit. In contrast to studies with PI-3K inhibitors, which inhibit all classes of PI-3Ks, the p85alpha regulatory subunit is not required for BCR-induced MEK1/2 and p42/44ERK phosphorylation, suggesting the contribution of another PI-3K family members in MEK1/2 and p42/44ERK activation. However, p85alpha(-/-) splenic B cells are defective in BCR-induced IkappaB kinase beta and IkappaBalpha phosphorylation. We demonstrate that NF-kappaB signaling is required for cyclin D2 induction via the BCR in normal B cells, implicating a possible link with the defective IkappaB kinase beta and IkappaBalpha phosphorylation in p85alpha(-/-) splenic B cells and their ability to induce cyclin D2. These results indicate that MEK1/2-p42/44ERK and NF-kappaB pathways link PI-3K activity to Ag receptor-mediated cyclin D2 induction in splenic B cells.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • B-Lymphocyte Subsets / enzymology*
  • B-Lymphocyte Subsets / immunology
  • B-Lymphocyte Subsets / metabolism
  • B-Lymphocyte Subsets / pathology
  • Cell Differentiation / immunology
  • Cyclin D2
  • Cyclins / antagonists & inhibitors
  • Cyclins / biosynthesis*
  • Cyclins / genetics
  • G1 Phase / genetics
  • G1 Phase / immunology
  • Gene Silencing / immunology
  • I-kappa B Kinase
  • I-kappa B Proteins / metabolism
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • MAP Kinase Signaling System / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase Kinases / physiology*
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / physiology*
  • Peptides / pharmacology
  • Phosphatidylinositol 3-Kinases / deficiency
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / physiology*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / physiology*
  • Receptors, Antigen, B-Cell / antagonists & inhibitors
  • Receptors, Antigen, B-Cell / physiology*
  • Recombinant Fusion Proteins / pharmacology
  • Retinoblastoma Protein / antagonists & inhibitors
  • Retinoblastoma Protein / metabolism
  • Spleen / enzymology
  • Spleen / immunology
  • Spleen / metabolism
  • Spleen / pathology

Substances

  • Ccnd2 protein, mouse
  • Cyclin D2
  • Cyclins
  • I-kappa B Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • Peptides
  • Phosphoinositide-3 Kinase Inhibitors
  • Receptors, Antigen, B-Cell
  • Recombinant Fusion Proteins
  • Retinoblastoma Protein
  • SN50 peptide
  • NF-KappaB Inhibitor alpha
  • MAP2K2 protein, human
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases
  • Chuk protein, mouse
  • I-kappa B Kinase
  • Ikbkb protein, mouse
  • Ikbke protein, mouse
  • MAP Kinase Kinase 1
  • MAP Kinase Kinase 2
  • MAP2K1 protein, human
  • Map2k1 protein, mouse
  • Mitogen-Activated Protein Kinase Kinases