Crosstalk between the extracellular domain of the ErbB2 receptor and IGF-1 receptor signaling.
Insulin-like growth factor 1 receptor (IGF-1R) plays an important role in cell growth and malignant transformation. To investigate IGF-1R-dependent signaling events and its effects on apoptosis induction and cellular proliferation, we generated a constitutively active, ligand-independent IGF-1R variant. We fused the cytoplasmic domain of the IGF-1R to the extracellular and transmembrane domains of the oncogenic ErbB2 receptor (ErbB2(V-->E)/IGF-1). A fusion protein in which the wild-type sequence of the ErbB2 receptor was used, served as a control (ErbB2(V)/IGF-1R). ErbB2(V)/IGF-1R, ErbB2(V-->E)/IGF-1R and IGF-1R were stably transfected into interleukin 3 (IL-3)-dependent BaF/3 cells. ErbB2(V-->E)/IGF-1R expressing cells exhibited ligand-independent, constitutive tyrosine phosphorylation of the receptor fusion protein. Constitutively, activated ErbB2(V-->E)/IGF-1R conferred IL-3 independence for growth and survival to the transfected BaF/3 cells. Constitutive activation of the IGF-1R results in cellular growth and protection against apoptosis upon IL-3 withdrawal in BaF/3 cells.
Belaus
Andrea
A
Georg Speyer Haus, Institute for Biomedical Research, Paul Ehrlich Street 42-44, 60596 Frankfurt am Main, Germany.
Merkle
Christian
C
Fritsche
Michael
M
Groner
Bernd
B
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D002455:Cell Division; D002462:Cell Membrane / Q000502:physiology; D002478:Cells, Cultured; D017931:DNA Primers; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D051379:Mice; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000502:physiology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection
D017931:DNA Primers; D007377:Interleukin-3; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D017526:Receptor, IGF Type 1; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins