Human pre-B cell receptor signal transduction: evidence for distinct roles of PI3kinase and MAP-kinase signalling pathways.
Pre-BCR acts as a critical checkpoint in B cell development. However, its signalling cascade still remains indistinctly characterised in human. We investigated pre-BCR signalling pathway to examine its regulation in normal primary pre-B lymphocytes and pre-B cell lines. In cell lines, early signalling events occurring after pre-BCR stimulation include phosphorylation of Lyn, Blk and Syk together with ZAP70, Btk, Vav, PLC-γ2 and various adaptor proteins, such as BLNK, LAB, LAT and SLP-76. Further downstream, these molecules induced activation of the PI3K/AKT and MAP-kinase resulting in an augmentation of canonical NF-κB pathways and cFos/AP1 activation. PI3K and MAPK exerted opposing effects on the pre-BCR-induced activation of the canonical NF-κB and c-Fos/AP1 pathways. Immediate nuclear export of FoxO3A and delayed import of IRF4 were additional events observed after pre-BCR crosslinking in primary cells. Pre-BCR-induced down-regulation of Rag1, Rag2, E2A and Pax5 transcripts occurred in a PI3K-dependent manner. Finally we bring evidence that pre-BCR stimulation or co stimulation with CD19 enhances cell cycle signal.
Inserm/UMR925, Université Picardie Jules Verne, Laboratoire d'Immunologie, UFR de Médecine 3, rue des Louvels, 80036, Amiens, France.
Kolandaswamy
K
Anbazhagan
Inserm/UMR925, Université Picardie Jules Verne, Laboratoire d'Immunologie, UFR de Médecine 3, rue des Louvels, 80036, Amiens, France.
Amrathlal
A
Rabbind Singh
Inserm/UMR925, Université Picardie Jules Verne, Laboratoire d'Immunologie, UFR de Médecine 3, rue des Louvels, 80036, Amiens, France.
Piec
P
Isabelle
Inserm/UMR925, Université Picardie Jules Verne, Laboratoire d'Immunologie, UFR de Médecine 3, rue des Louvels, 80036, Amiens, France.
Ibata
I
Stella
Inserm/UMR925, Université Picardie Jules Verne, Laboratoire d'Immunologie, UFR de Médecine 3, rue des Louvels, 80036, Amiens, France.
Alleaume-De Martel
AD
Céline
Inserm/UMR925, Université Picardie Jules Verne, Laboratoire d'Immunologie, UFR de Médecine 3, rue des Louvels, 80036, Amiens, France.
Eliane
E
Bissac
Inserm/UMR925, Université Picardie Jules Verne, Laboratoire d'Immunologie, UFR de Médecine 3, rue des Louvels, 80036, Amiens, France.
Brassart
B
Bertrand
Inserm/UMR925, Université Picardie Jules Verne, Laboratoire d'Immunologie, UFR de Médecine 3, rue des Louvels, 80036, Amiens, France.
Nyga
N
Rémy
CNRS/UMR 5535, Institut de Génétique Moléculaire de Montpellier 1919 Route de Mende, 34293, Montpellier, Cedex 5, France.
Taylor
T
Naomi
Inserm/UMR925, Université Picardie Jules Verne, Laboratoire d'Immunologie, UFR de Médecine 3, rue des Louvels, 80036, Amiens, France.
Fuentes
F
Vincent
Inserm/UMR925, Université Picardie Jules Verne, Laboratoire d'Immunologie, UFR de Médecine 3, rue des Louvels, 80036, Amiens, France.
Jacques
J
Rochette
Inserm/UMR925, Université Picardie Jules Verne, Laboratoire d'Immunologie, UFR de Médecine 3, rue des Louvels, 80036, Amiens, France.
Kaïss
K
Lassoued
MAPK; PI3K; pre-B cells; pre-BCR; receptor signalling