Molecular mechanism of B cell development governed by surrogate light chain.

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The preB cell receptor (preBCR), composed of muheavy chain, VpreB/lambda5 surrogate light chain and Igalpha/Igbeta heterodimer, is expressed transiently at the large preB cell stage of B cell development. Identification of molecules involved in the preBCR signaling is essential for elucidating the mechanism how preBCR governs B cell differentiation. In the present study, we have established a novel system that provides a superior way to analyze the signal transduction of preBCR by using bone marrow proB cells stimulated in vivo and ex vivo.When RAG-2^<-1-> mice were treated with an anti-Igbeta mAb, developmentally-arrested proB cells were induced to differentiate to the small preB cell stage. This indicates that the cross-linking of Igbeta on proB cells elicits differentiation signals analogouw to those delivered by preBCR in normal B cell development. The biochemical analyzes revealed that the cross-linking of Igbeta induced a rapid and transient tyrosine phosphorylation of Igalpha, Sky, P13-kinase, Vav and SLP-76 as well as the activation of MAP kinase ERK in proB cells. Intriguingly, the tyrosine phosphorylation of a protein (s) of 35-40kD was evident in proB cells stimulated with the anti-Igbeta mAb but not in B cells stimulated in the same way. We are in the process of identifying the nature of this molecule (s).We have cloned from preB cells a gene coding for a novel serine/threonine kinase, LOK,which is expressed predominantly in lymphocytes. LOK has a kinase domain, which shows some homology to that of a yeast MAPKKKK STE20 in yeast, as well as a proline-rich region and a coiled-coil region. In order to clarify the function of LOK in lymphocytes, we are currently establishing and analyzing mice deficient for LOK.