Absence of suppressor of cytokine signalling 3 reduces self-renewal and promotes differentiation in murine embryonic stem cells

Forrai, A; Boyle, K; Hart, AH; Hartley, L; Rakar, S; Willson, TA; Simpson, KM; Roberts, AW; Alexander, WS; Voss, AK; Robb, L

Author(s): Forrai, A; Boyle, K; Hart, AH; Hartley, L; Rakar, S; Willson, TA; Simpson, KM; Roberts, AW; Alexander, WS; Voss, AK; Robb, L;
Details: Publication Year 2006-03,Volume 24,Issue #3,Page 604-614
Journal Title: STEM CELLS
Publication Type: Journal Article
Abstract: Leukemia inhibitory factor (LIF) is required to maintain pluripotency and permit self-renewal of murine embryonic stem (ES) cells. LIF binds to a receptor complex of LIFR-beta and gp130 and signals via the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, with signalling attenuated by suppressor of cytokine signalling (SOCS) proteins. Recent in vivo studies have highlighted the role of SOCS-3 in the negative regulation of signalling via gp130. To determine the role of SOCS-3 in ES cell biology, SOCS-3-null ES cell lines were generated. When cultured in LIF levels that sustain self-renewal of wild-type cells, SOCS-3-null ES cell lines exhibited less self-renewal and greater differentiation into primitive endoderm. The absence of SOCS-3 enhanced JAK-STAT and extracellular signal-related kinase 1/2 (ERK-1/2)-mitogen-activated protein kinase (MAPK) signal transduction via gp130, with higher levels of phosphorylated STAT-1, STAT-3, SH-2 domain-containing cytoplasmic protein tyrosine phosphatase 2 (SHP-2), and ERK-1/2 in steady state and in response to LIF stimulation. Attenuation of ERK signalling by the addition of MAPK/ERK kinase (MEK) inhibitors to SOCS-3-null ES cell cultures rescued the differentiation phenotype, but did not restore proliferation to wild-type levels. In summary, SOCS-3 plays a crucial role in the regulation of the LIF signalling pathway in murine ES cells. Its absence perturbs the balance between activation of the JAK-STAT and SHP-2-ERK-1/2-MAPK pathways, resulting in less self-renewal and a greater potential for differentiation into the primitive endoderm lineage.
Publisher: ALPHAMED PRESS
Keywords: LEUKEMIA INHIBITORY FACTOR; IN-VITRO DIFFERENTIATION; RECEPTOR SUBUNIT GP130; PROTEIN-KINASE KINASE; SOCS-BOX MOTIF; ES CELLS; ENDODERM DIFFERENTIATION; HEMATOPOIETIC COMMITMENT; INTERLEUKIN-6 FAMILY; TARGETED DISRUPTION
Publisher's Version: https://doi.org/10.1634/stemcells.2005-0323
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Creation Date: 2006-03-01 12:00:00