CHOICE OF STATS AND OTHER SUBSTRATES SPECIFIED BY MODULAR TYROSINE-BASED MOTIFS IN CYTOKINE RECEPTORS

Many members of the cytokine receptor superfamily initiate intracellul ar signaling by activating members of the Jak family of tyrosine kinas es. Activation of the same Jaks by multiple cytokines raises the quest ion of how these cytokines activate distinct intracellular signaling p athways. Selection of particular substrates-the transcriptional activa tor Stat3 and protein tyrosine phosphatase PTP1D-that characterize res ponses to the ciliary neurotrophic factor-interleukin-6 cytokine famil y depended not on which Jak was activated, but was instead determined by specific tyrosine-based motifs in the receptor components-gp130 and LIFR-shared by these cytokines. Further, these tyrosine-based motifs were modular, because addition of a Stat3-specifying motif to another cytokine receptor, that for erythropoietin, caused it to activate Stat 3 in a ligand-dependent fashion.