THE CBL-RELATED PROTEIN CBLB PARTICIPATES IN FLT3 AND INTERLEUKIN-7 RECEPTOR SIGNAL-TRANSDUCTION IN PRO-B CELLS

The FLT3 receptor tyrosine kinase and its ligand, FL, play an importan t role in early hematopoietic development. We have found that CBLB, a recently characterized molecule closely related to the CBL protooncoge ne product, is phosphorylated on tyrosine(s) following FL treatment of JEA2 human pro-B cells and THP1 monocytic cells. Treatment of JEA2 ce lls with interleukin (IL)-7 induces CBLB phosphorylation as well. FL a nd IL-7, respectively, induce and increase association of tyrosine-pho sphorylated SHC and the p85 subunit of phosphatidylinositol 3'-kinase with CBLB. In these cells, CBLB constitutively binds the GRB2 adaptor predominantly through its N-terminal SH3 domain, to form a complex tha t is distinct from the GRB2.CBL and GRB2.SOS1 complexes. Together with the fact that CBLB is consistently found in blast cells from acute le ukemias and in peripheral blood mononuclear cells, this suggests that CBLB has a role in tyrosine kinase-regulated signaling pathways in man y hematolymphoid cells.