PKC-beta Controls I Kappa B Kinase Lipid Raft Recruitment and Activation in Response to BCR Signaling

Nat Immunol. 2002 Aug;3(8):780-6. doi: 10.1038/ni823. Epub 2002 Jul 15.

Abstract

NF-kappa B signaling is required for the maintenance of normal B lymphocytes, whereas dysregulated NF-kappa B activation contributes to B cell lymphomas. The events that regulate NF-kappa B signaling in B lymphocytes are poorly defined. Here, we demonstrate that PKC-beta is specifically required for B cell receptor (BCR)-mediated NF-kappa B activation. B cells from protein kinase C-beta (PKC-beta)-deficient mice failed to recruit the I kappa B kinase (IKK) complex into lipid rafts, activate IKK, degrade I kappa B or up-regulate NF-kappa B-dependent survival signals. Inhibition of PKC-beta promoted cell death in B lymphomas characterized by exaggerated NF-kappa B activity. Together, these data define an essential role for PKC-beta in BCR survival signaling and highlight PKC-beta as a key therapeutic target for B-lineage malignancies.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / immunology
  • B-Lymphocytes / enzymology
  • B-Lymphocytes / immunology*
  • Enzyme Inhibitors / pharmacology
  • Flow Cytometry
  • I-kappa B Kinase
  • I-kappa B Proteins / immunology
  • Immunoblotting
  • Indoles / pharmacology
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / immunology*
  • Lymphoma, B-Cell / immunology
  • Maleimides / pharmacology
  • Mesylates / pharmacology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • NF-kappa B / immunology*
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / immunology*
  • Protein Kinase C beta
  • Protein-Serine-Threonine Kinases / immunology*
  • Protein-Serine-Threonine Kinases / metabolism
  • Pyrroles / pharmacology
  • Receptors, Antigen, B-Cell / immunology*
  • Signal Transduction / immunology*

Substances

  • 5,21 - 12,17-dimetheneo-18H-dibenzo(i,o)pyrrolo(3,4-1)(1,8)diazacyclohexandecine-18,10(19H)dione,8((dimethylamino)methyl)-6,7,8,9,10,11-hexahydro,monomethanesulfonate
  • Enzyme Inhibitors
  • I-kappa B Proteins
  • Indoles
  • Isoenzymes
  • Maleimides
  • Mesylates
  • NF-kappa B
  • Pyrroles
  • Receptors, Antigen, B-Cell
  • Ro 31-8425
  • Protein-Serine-Threonine Kinases
  • Chuk protein, mouse
  • I-kappa B Kinase
  • Ikbkb protein, mouse
  • Ikbke protein, mouse
  • Protein Kinase C
  • Protein Kinase C beta