Coupling between p210bcr-abl and Shc and Grb2 adaptor proteins in hematopoietic cells permits growth factor receptor-independent link to ras activation pathway.

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Enforced expression of p210bcr-transforms interleukin 3 ()-dependent hematopoietic cell lines to growth factor-independent proliferation. It has been demonstrated that nonreceptor tyrosine kinase oncogenes may couple to the pathway to exert their transforming effect. In particular, p210bcr-was recently found to effect activation in hematopoietic cells. In this context, experiments were performed to evaluate signaling pathway by which p210bcr-might regulate . It was asked whether /, containing a -homology region 2 () domain, and known to function upstream from , might form specific complexes with p210bcr-and thus, possibly alter activity by coupling to the nucleotide exchange factor (/) through the protein-complex. This latter complex has been previously demonstrated to occur ubiquitously. We found that p210bcr-formed a specific complex with and with in three different cell lines transfected with a p210bcr-expression vector. There appeared to be a higher order complex containing , , and -proteins. In contrast to p210bcr-transformed cells, in which there was constitutive tight association between and , between and was (SLF)-dependent in a SLF-responsive, nontransformed parental cell line. The SLF-dependent association between and in nontransformed cells involved formation of a complex of with receptor after SLF treatment. Thus, p210bcr-appears to function in a hematopoietic activation pathway to allow growth factor-independent coupling between , which exists in a complex with the nucleotide exchange factor (), and . may not be required for -interaction, because it fails to bind strongly to .

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Animals Mice Bone Marrow Cells Hematopoietic Stem Cells Cells, Cultured Tyrosine Adaptor Proteins, Signal Transducing Oncogene Protein p21(ras Proteins Receptor, Epidermal Growth Factor