PMID: 8950973Nov 21, 1996Paper

Discrete protein interactions with the Grb2/c-Cbl complex in SCF- and TPO-mediated myeloid cell proliferation

Oncogene
M F BrizziL Pegoraro

Abstract

Hemopoietic cell proliferation is mediated by non-tyrosine and tyrosine kinases that signal via uncommon and common sets of downstream effector molecules including the Grb2/c-Cbl. In the present study we evaluated tyrosine phosphorylation of c-Cbl and the interaction of the Grb2/c-Cbl complex with signaling proteins upon activation of non-tyrosine (c-Mpl) and tyrosine kinase (c-Kit) receptors leading to myeloid cell proliferation. By using the growth factor dependent M-07e cell line, we found that both c-Mpl and c-Kit ligands, namely: SCF and TPO, induce c-Cbl tyrosine phosphorylation. In these cells the adaptor protein Grb2 constitutively binds a substantial fraction of c-Cbl through the N-terminal SH3 domain. In vitro experiments showed that the stable Grb2/c-Cbl complex interacts, through the Grb2 SH2 domain, with the SCF-activated c-Kit. By contrast stimulation with TPO leads to the formation of a Grb2 complex containing JAK2. In vitro and in vivo experiments support the hypothesis that Grb2 mediates the association of c-Kit with c-Cbl. Moreover we found that, upon SCF stimulation, the Grb2/c-Cbl complex recruits Shc, probably via Grb2. By contrast the Ras exchanger factor (Sos1) was not detected in anti-c-Cbl immunoprecipi...Continue Reading

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