MUTATIONAL ANALYSIS OF A CRITICAL SIGNALING DOMAIN OF THE HUMAN INTERLEUKIN-4 RECEPTOR

The human interleukin 4 receptor (hIL-4R) is a member of a superfamily of cytokine receptors defined by conserved features of their extracel lular domains. The intracellular domains of the hIL- 4R and of other m embers of this family lack any recognizable enzymatic motifs, though l igand-dependent tyrosine phosphorylation of these receptors has been o bserved. Recent studies have suggested that serine-rich and acidic dom ains within the cytoplasmic portions of cytokine receptors might be re quired for signal transduction. Using deletion and truncation mutants of the hIL-4R, we have explored an essential 39-amino acid signaling d omain that is rich in acidic amino acid residues and in serine residue s that form consensus phosphorylation sites for known serine/threonine kinases. To assess the contribution of these moths to signaling, we e ngineered site directed mutants of these residues. Surprisingly, cells expressing mutant hIL-4R lacking either the serine or the acidic amin o acids retain the ability of cells expressing the wild-type receptor to proliferate in hIL-4. Furthermore, receptors in which all six cytop lasmic tyrosines are absent can function, suggesting that tyrosine pho sphorylation of the receptor may be an epiphenomenon rather than a req uisite event in signaling.