A tyrosine-phosphorylated protein of 140 kD is constitutively associated with the phosphotyrosine binding domain of Shc and the SH3 domains of Grb2 in acute myeloid leukemia cells.
The Shc gene encodes three proteins that have been implicated as mediators of signal transduction from growth factor receptors and nonreceptor tyrosine kinases to Ras. Overexpression of Shc in established murine fibroblasts results in oncogenic transformation, indicating that Shc has oncogenic potential. Shc proteins contain a carboxy terminal SH2 domain and a novel non-SH2 phosphotyrosine-binding (PTB) domain that specifically recognizes a phosphorylated NPXpY motif in target proteins such as the epidermal growth factor receptor. We show here that Shc is constitutively tyrosine-phosphorylated in all primary acute myeloid leukemias analyzed and that, in some of these leukemias, Shc is associated through its PTB domain with a tyrosine-phosphorylated protein of 140 kD (p140) in vivo. In factor-dependent cells, this 140-kD protein can be tyrosine-phosphorylated in vitro in response to cytokines involved in myeloid proliferation and differentiation, ie, granulocyte-macrophage colony-stimulating factor and colony-stimulating factor-1. A similar or identical protein of 140 kD is constitutively bound to the C-terminal SH3 domain of Grb2 in the same acute myeloid leukemias. In addition to p140, other tyrosine-phosphorylated proteins of 61 and 200 kD are constitutively associated with Shc in some of the leukemias analyzed. Our results implicate Shc, Grb2, p140, and additional tyrosine-phosphorylated proteins of 61 and 200 kD in signalling of acute myeloid leukemia cells.
Jücker
M
M
Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore 21201, USA.
Schiffer
C A
CA
Feldman
R A
RA
D000208:Acute Disease; D000818:Animals; D066246:ErbB Receptors / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute; D007951:Leukemia, Myeloid / Q000378:metabolism*; D051379:Mice; D008970:Molecular Weight; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism*; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D014407:Tumor Cells, Cultured; D018909:src Homology Domains
D011518:Proto-Oncogene Proteins; D017475:Receptors, Nerve Growth Factor; D019000:Phosphotyrosine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA