Biological effects of c-Mer receptor tyrosine kinase in hematopoietic cells depend on the Grb2 binding site in the receptor and activation of NF-kappa B

The c-Mer receptor tyrosine kinase (RTK) is most closely related to chicken c-Eyk and belongs to the Axl RTK subfamily. Although not detected in norma l lymphocytes, c-Mer is expressed in B- and T-cell leukemia cell lines, sug gesting an association with lymphoid malignancies. To gain an understanding of the role of this receptor in lymphoid cells, we expressed in murine int erleukin-3 (IL-3)-dependent Ba/F3 pro-B-lymphocyte cells a constitutively a ctive receptor, CDMer, formed from the CD8 extracellular domain and the c-M er intracellular domain. Cells transfected with a plasmid encoding the CDMe r receptor became IL-3 independent. When tyrosine (Y)-to-phenylalanine (F) mutations were introduced into c-Iller, only the Y867 change significantly reduced the IL-3-independent cell proliferation. The Y867 residue in the CD Mer receptor mediated the binding of Grb2, which recruited the p85 phosphat idylinositol 3-kinase (PI 3-kinase). Despite the difference in promotion of proliferation, both the CDMer and mutant F867 receptors activated Erk in t ransfected cells. On the other hand, we found that both transcriptional act ivation of NF-KB and activation of PI 3-kinase were significantly suppresse d with the F867 mutant receptor, suggesting that the activation of antiapop totic pathways is the major mechanism for the observed phenotypic differenc e. Consistent with this notion, apoptosis induced by IL-3 withdrawal was st rongly prevented by CDMer but not by the F867 mutant receptor.