An epidermal growth factor receptor/ret chimera generates mitogenic and transforming signals: evidence for a ret-specific signaling pathway.
A chimeric expression vector which encoded for a molecule encompassing the extracellular domain of the epidermal growth factor (EGF) receptor (EGFR) and the intracellular domain of the ret kinase (EGFR/ret chimera) was generated. Upon ectopic expression in mammalian cells, the EGFR/ret chimera was correctly synthesized and transported to the cell surface, where it was shown capable of binding EGF and transducing an EGF-dependent signal intracellularly. Thus, the EGFR/ret chimera allows us to study the biological effects and biochemical activities of the ret kinase under controlled conditions of activation. Comparative analysis of the growth-promoting activity of the EGFR/ret chimera expressed in fibroblastic or hematopoietic cells revealed a biological phenotype clearly distinguishable from that of the EGFR, indicating that the two kinases couple with mitogenic pathways which are different to some extent. Analysis of biochemical pathways implicated in the transduction of mitogenic signals also evidenced significant differences between the ret kinase and other receptor tyrosine kinases. Thus, the sum of our results indicates the existence of a ret-specific pathway of mitogenic signaling.
Santoro
M
M
Centro di Endocrinologia ed Oncologia Sperimentale del Consiglio Nazionale delle Ricerche, Università degli Studi di Napoli, Italy.
Wong
W T
WT
Aroca
P
P
Santos
E
E
Matoskova
B
B
Grieco
M
M
Fusco
A
A
di Fiore
P P
PP
D016475:3T3 Cells / Q000166:cytology / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002455:Cell Division / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D004247:DNA / Q000235:genetics; D029721:Drosophila Proteins; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D020690:GTPase-Activating Proteins; D006801:Humans; D007294:Inositol / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D010743:Phospholipids / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014170:Transformation, Genetic
D029721:Drosophila Proteins; D020690:GTPase-Activating Proteins; D010743:Phospholipids; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D007294:Inositol; D004247:DNA; D066246:ErbB Receptors; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse; D017346:Protein Serine-Threonine Kinases