Specific association of phosphatidylinositol 3‐kinase with the protooncogene product Cbl in Fcγ receptor signaling

Cbl functions downstream of Src kinases in FCγRI signaling in primary human macrophages

“…Fc␥RI-induced Cbl tyrosine phosphorylation in the BMHM was rapid and transient, similar to that described in mouse peritoneal macrophages and human myeloid cell lines [8,[10][11][12] (Fig. 1).…”

“…The Cbl adaptor protein is a major substrate for tyrosine kinases in several myeloid cell lines and in mouse peritoneal macrophages after stimulation of Fc␥ receptors [8][9][10][11][12]. Antiphosphotyrosine blotting of Cbl immunoprecipitates from BMHM shows that Cbl was rapidly and transiently tyrosine phosphorylated on specific ligation of the Fc␥RI receptor (Fig.…”

“…Following stimulation of Fc␥ receptors and the ensuing tyrosine phosphorylation of Cbl, Cbl becomes complexed with several kinases and adaptor proteins [8][9][10][11]. To examine which additional proteins were associated with Cbl in the BMHM, we stimulated BMHM by cross-linking of the Fc␥RI receptor followed by immunoprecipitation of Cbl from the cell lysates and subsequent Western blotting (Figs.…”

“…Fc receptors are unique in that they do not possess intrinsic kinase activity, but mediate downstream signaling events through a conserved stretch of amino acids, the immunoreceptor tyrosine-based activation motif (ITAM), which resides in the cytoplasmic region of the associated ␥-chains [3][4][5][6][7]. Fc receptor activation is associated with rapid tyrosine phosphorylation of multiple cellular proteins including the adaptor protein, Cbl, which is complexed with the ␥-subunit of Fc␥RI [8][9][10][11][12].…”

“…Since its cloning, Cbl has been studied mostly in cell lines [9, 15, 23, 24, 31-35, 38, 49], with only a few reports describing Cbl interactions in non-human [8,46,50] or human [20,24] primary cells. Although several groups have published reports on Cbl interactions in Fc receptor signaling [8][9][10], little has been published about the function of Cbl following specific activation of the high-affinity Fc␥RI receptor for monomeric IgG (CD64) and, to date, this interaction has not been studied in detail in primary human macrophages. In addition, although the CrkL-Cbl interaction has been studied in transformed cells [11,20,32,[38][39][40]51] and in responses to EGF [20,52] and T cell receptor activation [24,47], little is known about the CrkL-Cbl association in Fc receptor signal transduction in normal hematopoietic cells.…”