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.
Su
Yu-Wen
YW
Institute for Biology III, Albert-Ludwigs University of Freiburg and Max Planck Institute for Immunobiology, Freiburg, Germany.
Herzog
Sebastian
S
Lotz
Michael
M
Feldhahn
Niklas
N
Müschen
Markus
M
Jumaa
Hassan
H
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D001402:B-Lymphocytes / Q000166:cytology / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D002455:Cell Division / Q000502:physiology*; D017930:Genes, Reporter; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C110810:LAT protein, human; D008565:Membrane Proteins; D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; D014443:Tyrosine