Convergence of signaling pathways on the activation of ERK in B cells.
The B cell receptor (BCR) initiates three major signaling pathways: the Ras pathway, which leads to extracellular signal-regulated kinase (ERK) activation; the phospholipase C-gamma pathway, which causes calcium mobilization; and the phosphoinositide 3-kinase (PI 3-kinase) pathway. These combine to induce different biological responses depending on the context of the BCR signal. Both the Ras and PI 3-kinase pathways are important for B cell development and activation. Several model systems show evidence of cross-regulation between these pathways. Here we demonstrate through the use of PI 3-kinase inhibitors and a dominant-negative PI 3-kinase construct that the BCR-induced phosphorylation and activation of ERK is dependent on PI 3-kinase. PI 3-kinase feeds into the Ras signaling cascade at multiple points, both upstream and downstream of Ras. We also show that ERK activation is dependent on phospholipase C-gamma, in keeping with its dependence on calcium mobilization. Last, the activation of PI 3-kinase itself is completely dependent on Ras. We conclude that the PI 3-kinase and Ras signaling cascades are intimately connected in B cells and that the activation of ERK is a signal integration point, since it requires simultaneous input from all three major signaling pathways.
Jacob
Anand
A
Oklahoma Medical Research Foundation, Immunobiology and Cancer Program, Oklahoma City, Oklahoma 73104, USA.
Cooney
Damon
D
Pradhan
Madhura
M
Coggeshall
K Mark
KM
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation; D051380:GRB2 Adaptor Protein; D007527:Isoenzymes / Q000502:physiology; D048728:MAP Kinase Kinase Kinase 1; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D051966:Phospholipase C gamma; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011506:Proteins / Q000502:physiology; D011947:Receptors, Antigen, B-Cell / Q000502:physiology; D010738:Type C Phospholipases / Q000502:physiology; D018631:ras Proteins / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; D007527:Isoenzymes; D048728:MAP Kinase Kinase Kinase 1; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D051966:Phospholipase C gamma; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D011947:Receptors, Antigen, B-Cell; D010738:Type C Phospholipases; D018631:ras Proteins; C495949:Grb2 protein, mouse; C482578:Map3k1 protein, mouse