The carboxyl-terminal domains of gp130-related cytokine receptors are necessary for suppressing embryonic stem cell differentiation - Involvement of STAT3

Citation
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
Citations number
47
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
00219258 → ACNP
Volume
274
Issue
14
Year of publication
1999
Pages
9729 - 9737
Database
ISI
SICI code
0021-9258(19990402)274:14<9729:TCDOGC>2.0.ZU;2-2
Abstract
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.