Distinct sequence motifs within the cytoplasmic domain of the human IL-4 receptor differentially regulate apoptosis inhibition and cell growth.

Hematopoietin receptors generally function as multimeric complexes composed of a unique ligand-binding chain and a second component often shared between several members of this receptor family. To better understand the signal transduction of the human IL-4 receptor (hIL4R), we analyzed the functionality of targeted mutations in two cytoplasmic regions of the ligand-binding hIL4R chain that we previously identified to be necessary for growth mediation in factor-dependent murine Ba/F3 cells. Here, we provide evidence that transient inhibition of apoptotic death of Ba/F3 cells and the competence to proliferate indefinitely depend on separated and distinct sequence motifs of the hIL4R. In particular, hIL4R constructs with a truncation of the recently described gp130 box1 from P242 to K264, or a deletion of the acidic region between S330 and S365, fail to stimulate growth or to mediate the inhibition of apoptosis. hIL4R bearing a point mutation within the gp130 box1 (P242S) is defective for growth stimulation but still signals the transient inhibition of apoptotic cell death and the induction of c-myc RNA. A third region required for IL4-mediated cell growth is localized between T462 and S476 and includes the sequence NPAY previously described to serve as interaction motif in signaling of epidermal growth factor and insulin receptors. Conversion of Y472 into F472 within the latter hIL4R motif affects the competence of stably transfected BA/F3 cells to proliferate indefinitely in the presence of hIL4. Sequences C-terminal of S476 are not essential for growth stimulation of BA/F3 transfectants.