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Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A human cytoplasmic signaling protein has been cloned that possesses the same structural arrangement of SH3-SH2-SH3 domains as Grb2. This protein is designated Grap for Grb2-related adaptor protein. The single 2.3-kilobase (kb) grap transcript was expressed predominantly in thymus and spleen, while the ubiquitously expressed grb2 gene produced two mRNA species of 3.8 and 1.5 kb. Grap and Grb2 consist of 217 amino acids and share 59% amino acid sequence identity, with highest homology in the N-terminal SH3 domain. The GrapSH2 domain interacts with ligand-activated receptors for stem cell factor (c-kit) and erythropoietin (EpoR). Grap also forms a stable complex with the Bcr-Abl oncoprotein via its SH2 domain in K562 cells. Furthermore, Grap is associated with a Ras guanine nucleotide exchange factor mSos1, primarily through its N-terminal SH3 domain. These results show that a family of Grb2-like proteins exist and couple signals from receptor and cytoplasmic tyrosine kinases to the Ras signaling pathway.
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PMID:Grap is a novel SH3-SH2-SH3 adaptor protein that couples tyrosine kinases to the Ras pathway. 864 2

Shc proteins are important substrates of receptor and cytoplasmic tyrosine kinases that couple activated receptors to downstream signaling enzymes. Phosphorylation of Shc tyrosine residues 239 and 317 leads to recruitment of the Grb2-Sos complex, thus linking Shc phosphorylation to Ras activation. We have used phosphorylated peptides corresponding to the regions spanning tyrosine 239/240 and 317 of Shc in an expression library screen to identify additional downstream targets of Shc. Here we report the identification of Gads, a novel adaptor protein most similar to Grb2 and Grap that contains amino and carboxy terminal SH3 domains flanking a central SH2 domain and a 120 amino acid unique region. Gads is most highly expressed in the thymus and spleen of adult animals and in human leukemic cell lines. The binding specificity of the Gads SH2 domain is similar to Grb2 and mediates the interaction of Gads with Shc, Bcr-Abl and c-kit. Gads does not interact with Sos, Cbl or Sam68, although the isolated carboxy terminal Gads SH3 domain is able to bind these molecules in vitro. Our results suggest that the unique structure of Gads regulates its interaction with downstream SH3 domain-binding proteins and that Gads may function to couple tyrosine-phosphorylated proteins such as Shc, Bcr-Abl and activated receptor tyrosine kinases to downstream effectors distinct from Sos and Ras.
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PMID:Gads is a novel SH2 and SH3 domain-containing adaptor protein that binds to tyrosine-phosphorylated Shc. 987 23