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(Received for publication, May 14, 1996, and in revised form, August 28, 1996)
From the Ludwig Institute for Cancer Research, Melbourne Tumour
Biology Branch, P.O. Royal Melbourne Hospital, Victoria 3050, Australia
The leukemia inhibitory factor/interleukin 6 (LIF/IL6) family of cytokines promotes cell type-specific pleiotropic
effects by engaging multimeric receptor complexes that share the common affinity converter/signal transducing subunit gp130. While the maintenance of embryonic stem (ES) cell self-renewal is an activity unique to this family of cytokines, the intracellular signaling events
mediated by gp130 remain largely unknown. Here we show a rapid and
transient increase in the specific activity of the Src-related kinase
Hck as well as of the Janus kinases Jak1, Jak2, and Tyk2 following
treatment of ES cells with LIF or a combination of IL6 plus a soluble
form of the IL6 receptor. Within 2 min of stimulation, we also observed
increased tyrosine phosphorylation of SHC, activation of the guanidine
nucleotide exchange activity on p21ras, and an electrophoretic
mobility shift of MAP kinase. Functional involvement of Hck and
p21ras activation in gp130-mediated signaling is supported by
the finding that the introduction of constitutively activated Hck or
v-Ha-ras partially alleviates the requirement of ES cells
for LIF to remain undifferentiated. In contrast, suppression of Jak1 in
ES cells by antisense technology increased the amount of LIF required
to retain their pluripotentiality. These results are consistent with the notion that gp130-mediated suppression of ES cell differentiation depends on signaling through at least two cascades, namely a
p21ras-dependent pathway that possibly involves
Hck, as well as a Jak kinase-dependent pathway.
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