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

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Abstract
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.