The molecular requirements for LAT-mediated differentiation and the role of LAT in limiting pre-B cell expansion.

Successful recombination of the heavy-chain locus in developing B cells results in the expression of the pre-BCR, which induces the proliferation and expansion of pre-B cells. To avoid uncontrolled proliferation, pre-BCR signals transmitted via the adaptor protein SLP-65 (SH2-domain-containing leukocyte protein of 65 kDa) lead to the down-regulation of pre-BCR expression and to pre-B cell differentiation. Here, we show that, similarly to SLP-65, the adaptor protein LAT (linker for activation of T cells) limits pre-B cell proliferation and reduces the potential of a tumorgenic pre-B cell line to develop leukemia in immune-deficient mice. We further show that the four distal tyrosines are required for LAT activity in pre-B cells. Mutation at Y136 completely abolishes LAT activity, whereas single point-mutations at Y175, Y195 or Y235 impair, but do not block, LAT-induced pre-B cell differentiation. As LAT is also expressed in human pre-B cells, our results suggest that LAT cooperates with SLP-65 to promote the differentiation and control the proliferation of both murine and human pre-B cells.