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

Autor: Boswell Hs, T Tauchi, D. S. Leibowitz, Hal E. Broxmeyer
Rok vydání: 1994
Předmět:
Src Homology 2 Domain-Containing
Transforming Protein 1
Immunology
Fusion Proteins
bcr-abl
Bone Marrow Cells
Oncogene Protein p21(ras)
Biology
Hematopoietic Cell Growth Factors
Mice
Growth factor receptor
Proto-Oncogene Proteins
Receptors
Colony-Stimulating Factor
Animals
Immunology and Allergy
Phosphorylation
Cells
Cultured
Adaptor Proteins
Signal Transducing
Cell Line
Transformed
GRB2 Adaptor Protein
Stem Cell Factor
Proteins
Receptor Protein-Tyrosine Kinases
Signal transducing adaptor protein
Articles
Hematopoietic Stem Cells
Precipitin Tests
Cell biology
ErbB Receptors
Adaptor Proteins
Vesicular Transport
Proto-Oncogene Proteins c-kit
Shc Signaling Adaptor Proteins
Cancer research
biology.protein
Tyrosine
GRB2
Guanine nucleotide exchange factor
biological phenomena
cell phenomena
and immunity
Signal transduction
Zdroj: The Journal of Experimental Medicine
ISSN: 1540-9538
0022-1007
DOI: 10.1084/jem.179.1.167
Popis: Enforced expression of p210bcr-abl transforms interleukin 3 (IL-3)-dependent hematopoietic cell lines to growth factor-independent proliferation. It has been demonstrated that nonreceptor tyrosine kinase oncogenes may couple to the p21ras pathway to exert their transforming effect. In particular, p210bcr-abl was recently found to effect p21ras activation in hematopoietic cells. In this context, experiments were performed to evaluate a protein signaling pathway by which p210bcr-abl might regulate p21ras. It was asked whether Shc p46/p52, a protein containing a src-homology region 2 (SH2) domain, and known to function upstream from p21ras, might form specific complexes with p210bcr-abl and thus, possibly alter p21ras activity by coupling to the guanine nucleotide exchange factor (Sos/CDC25) through the Grb2 protein-Sos complex. This latter complex has been previously demonstrated to occur ubiquitously. We found that p210bcr-abl formed a specific complex with Shc and with Grb2 in three different murine cell lines transfected with a p210bcr-abl expression vector. There appeared to be a higher order complex containing Shc, Grb2, and bcr-abl proteins. In contrast to p210bcr-abl transformed cells, in which there was constitutive tight association between Grb2 and Shc, binding between Grb2 and Shc was Steel factor (SLF)-dependent in a SLF-responsive, nontransformed parental cell line. The SLF-dependent association between Grb2 and Shc in nontransformed cells involved formation of a complex of Grb2 with c-kit receptor after SLF treatment. Thus, p210bcr-abl appears to function in a hematopoietic p21ras activation pathway to allow growth factor-independent coupling between Grb2, which exists in a complex with the guanine nucleotide exchange factor (Sos), and p21ras. Shc may not be required for Grb2-c-kit interaction, because it fails to bind strongly to c-kit.
Databáze: OpenAIRE
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