DIFFERENTIAL ACTIVATION OF ACUTE-PHASE RESPONSE FACTOR STAT3 AND STAT1 VIA THE CYTOPLASMIC DOMAIN OF THE INTERLEUKIN-6 SIGNAL TRANSDUCER GP130 .1. DEFINITION OF A NOVEL PHOSPHOTYROSINE MOTIF MEDIATING STAT1 ACTIVATION/

Interleukin-6 (IL-6) and gamma-interferon (IFN gamma) activate an over lapping set of genes via the Jak/STAT pathway, However, at least in hu man cells, a differential activation of STAT transcription factors was observed: IL-6 activates both acute phase response factor (APRF)/STAT 3 and STAT1, whereas IFN gamma leads only to STAT1 activation, All STA Ts cloned so far contain SH2 domains, Since all cytokine receptors usi ng the Jak/STAT pathway were found to be tyrosine-phosphorylated after ligand binding, it has been proposed that specific phosphotyrosine mo dules within the cytoplasmic domain of the receptor chains recruit dif ferent STAT factors. We have analyzed by mutational studies and by pho sphopeptide competition assays which of the tyrosine modules of the IL -6 signal transducer gp130 are capable of recruiting either APRF or ST AT1, We found that two of the four tyrosine modules that are important for APRF activation also activate STAT1. For these modules, we propos e the new consensus sequence YXPQ. We further present evidence that ST AT1 is activated independently from APRF suggesting that gp130 contain s multiple independent STAT binding sites, We compare the APRF and STA T1 activation motifs of gp130 with the STAT1 activation moth of the IF N gamma receptor and demonstrate that the specificity of activation ca n be changed from APRF to STAT1 and vice versa by only two point mutat ions within a tyrosine module. These data strongly support the concept that the activation of a specific STAT is determined mainly by the ph osphotyrosine module, The significance of these findings for other rec eptor systems is discussed.