Differential Roles for Extracellularly Regulated Kinase-Mitogen-Activated Protein Kinase in B Cell Antigen Receptor-Induced Apoptosis and CD40-Mediated Rescue of WEHI-231 Immature B Cells

The entry of B lymphocytes into secondary lymphoid organs is a critical step in the development of an immune response, providing a site for repertoire shaping, antigen-induced activation and selection. These events are controlled by signals generated through the B cell antigen receptor (BCR) and are associated with changes in the migration properties of B cells in response to chemokine gradients. The chemokine stromal cell–derived factor (SDF)-1α is thought to be one of the driving forces during those processes, as it is produced inside secondary lymphoid organs and induces B lymphocyte migration that arrests upon BCR engagement. The signaling pathway that mediates this arrest was genetically dissected using B cells deficient in specific BCR-coupled signaling components. BCR-induced inhibition of SDF-1α chemotaxis was dependent on Syk, BLNK, Btk, and phospholipase C (Plc)γ2 but independent of Ca2+ mobilization, suggesting that the target of BCR stimulation was a protein kinase C (PKC)-dependent substrate. This target was identified as the SDF-1α receptor, CXCR4, which undergoes PKC- dependent internalization upon BCR stimulation. Mutation of the internalization motif SSXXIL in the COOH terminus of CXCR4 resulted in B cells that constitutively expressed this receptor upon BCR engagement. These studies suggest that one pathway by which BCR stimulation results in inhibition of SDF-1α migration is through PKC-dependent downregulation of CXCR4.

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Phosphatidylinositol 3-Kinase-Dependent Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase 1/2 and NF-κB Signaling Pathways Are Required for B Cell Antigen Receptor-Mediated Cyclin D2 Induction in Mature B Cells

The Journal of Immunology ◽

10.4049/jimmunol.172.5.2753 ◽

2004 ◽

Vol 172 (5) ◽

pp. 2753-2762 ◽

Cited By ~ 17

Author(s):

Michael J. Piatelli ◽

Carrie Wardle ◽

Joseph Blois ◽

Cheryl Doughty ◽

Brian R. Schram ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Signaling Pathways ◽

B Cell Antigen Receptor ◽

Phosphatidylinositol 3 Kinase ◽

Cell Antigen Receptor ◽

Extracellular Signal Regulated Kinase ◽

Cell Antigen ◽

Extracellular Signal ◽

Mitogen Activated Protein

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Protein Kinase C β Controls Nuclear Factor κB Activation in B Cells Through Selective Regulation of the IκB Kinase α

Journal of Experimental Medicine ◽

10.1084/jem.20020408 ◽

2002 ◽

Vol 195 (12) ◽

pp. 1647-1652 ◽

Cited By ~ 174

Author(s):

Kaoru Saijo ◽

Ingrid Mecklenbräuker ◽

Angela Santana ◽

Michael Leitger ◽

Christian Schmedt ◽

...

Keyword(s):

Protein Kinase C ◽

B Cells ◽

Protein Kinase ◽

Tyrosine Kinase ◽

B Cell ◽

B Cell Antigen Receptor ◽

Nuclear Factor ◽

Cell Antigen ◽

Kinase C ◽

Iκb Kinase

Activation of the nuclear factor (NF)-κB transcription complex by signals derived from the surface expressed B cell antigen receptor controls B cell development, survival, and antigenic responses. Activation of NF-κB is critically dependent on serine phosphorylation of the IκB protein by the multi-component IκB kinase (IKK) containing two catalytic subunits (IKKα and IKKβ) and one regulatory subunit (IKKγ). Using mice deficient for protein kinase C β (PKCβ) we show an essential role of PKCβ in the phosphorylation of IKKα and the subsequent activation of NF-κB in B cells. Defective IKKα phosphorylation correlates with impaired B cell antigen receptor–mediated induction of the pro-survival protein Bcl-xL. Lack of IKKα phosphorylation and defective NF-κB induction in the absence of PKCβ explains the similarity in immunodeficiencies caused by PKCβ or IKKα ablation in B cells. Furthermore, the well established functional cooperation between the protein tyrosine kinase Bruton's tyrosine kinase (Btk), which regulates the activity of NF-κB and PKCβ, suggests PKCβ as a likely serine/threonine kinase component of the Btk-dependent NF-κB activating signal transduction chain downstream of the BCR.

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Cutting Edge: Differential Sequestration of Plasma Membrane-Associated B Cell Antigen Receptor in Mature and Immature B Cells into Glycosphingolipid-Enriched Domains

The Journal of Immunology ◽

10.4049/jimmunol.166.2.736 ◽

2001 ◽

Vol 166 (2) ◽

pp. 736-740 ◽

Cited By ~ 53

Author(s):

James B. Chung ◽

Mark A. Baumeister ◽

John G. Monroe

Keyword(s):

Plasma Membrane ◽

B Cells ◽

B Cell ◽

Antigen Receptor ◽

Cutting Edge ◽

B Cell Antigen Receptor ◽

Cell Antigen Receptor ◽

Cell Antigen ◽

Immature B Cells

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BAFF regulates B cell survival by downregulating the BH3-only family member Bim via the ERK pathway

Journal of Experimental Medicine ◽

10.1084/jem.20051283 ◽

2005 ◽

Vol 202 (10) ◽

pp. 1363-1374 ◽

Cited By ~ 137

Author(s):

Andrew Craxton ◽

Kevin E. Draves ◽

Adriana Gruppi ◽

Edward A. Clark

Keyword(s):

B Cells ◽

B Cell ◽

Cell Survival ◽

Mitogen Activated Protein Kinase ◽

Marginal Zone B Cells ◽

B Cell Survival ◽

Extracellular Signal ◽

Mitogen Activated Protein ◽

B Cell Homeostasis ◽

Induced Apoptosis

The B cell activating factor belonging to the tumor necrosis factor family (BAFF) is required for B cell survival and maturation. The mechanisms by which BAFF mediates B cell survival are less understood. We found that BAFF and a proliferation-inducing ligand (APRIL), which are related, block B cell antigen receptor (BCR)–induced apoptosis upstream of mitochondrial damage, which is consistent with a role for Bcl-2 family proteins. BCR ligation strongly increased expression of the proapoptotic Bcl-2 homology 3–only Bcl-2 protein Bim in both WEHI-231 and splenic B cells, and increases in Bim were reversed by BAFF or APRIL. Small interfering RNA vector–mediated suppression of Bim blocked BCR-induced apoptosis. BAFF also induced Bim phosphorylation and inhibited BCR-induced association of Bim with Bcl-2. BAFF induced delayed but sustained stimulation of extracellular signal–regulated kinase (ERK) and its activators, mitogen-activated protein kinase/ERK activating kinase (MEK) and c-Raf, and MEK inhibitors promoted accumulation and dephosphorylation of Bim. These results suggest that BAFF inhibits BCR-induced death by down-regulating Bim via sustained ERK activation, demonstrating that BAFF directly regulates Bim function. Although transitional immature type 1 (T1) B cell numbers are normal in Bim−/− mice, T2 and follicular mature B cells are elevated and marginal zone B cells are reduced. Our results suggest that mature B cell homeostasis is maintained by BAFF-mediated regulation of Bim.

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