The carboxyl-terminal domains of gp130-related cytokine receptors are necessary for suppressing embryonic stem cell differentiation - Involvement of STAT3
M. Ernst et al., The carboxyl-terminal domains of gp130-related cytokine receptors are necessary for suppressing embryonic stem cell differentiation - Involvement of STAT3, J BIOL CHEM, 274(14), 1999, pp. 9729-9737
Cell type-specific responses to the leukemia inhibitory factor (LIF)/interl
eukin 6 cytokine family are mediated by dimerization of the LIF receptor al
pha-chain (LIFR alpha) with the signal transducer gp130 or of two gp130 mol
ecules followed by activation of the JAK/STAT and Ras/mitogen-activated pro
tein kinase cascades. In order to dissect the contribution of gp130 and LIF
R alpha individually, chimeric molecules consisting of the extracellular do
main of the granulocyte colony stimulating factor receptor (GCSF-R) and var
ious mutant forms of the cytoplasmic domains of gp130 or LIFR alpha were ex
pressed in embryonic stem (ES) cells to test for suppression of differentia
tion, or in a factor-dependent plasma cytoma cell line to assess for induct
ion of proliferation. Carboxyl-terminal domains downstream of the phosphata
se (SHP2)-binding sites were dispensable for mitogen-activated protein kina
se activation and the transduction of proliferative signals. Moreover, carb
oxyl-terminal truncation mutants which lacked intact Box 3 homology domains
showed decreased STAT3 activation, failed to induce Hck kinase activity an
d suppress ES cell differentiation. Moreover, STAT3 antisense oligonucleoti
des impaired LIF-dependent inhibition of differentiation. Substitution of t
he tyrosine residue within the Box 3 region of the GSCF-R abolished recepto
r-mediated suppression of differentiation without affecting the transductio
n of proliferative signals. Thus, distinct cytoplasmic domains within the L
IFR alpha, gp130, and GCSF-R transduce proliferative and differentiation su
ppressing signals.