Leukemia Inhibitory Factor Receptor Activates Signaling Pathways with Opposite Roles within Different Regions
While receiving the signal from environment to grow for self-renewal, stem cells also need a mechanism to stop the signal either for taking a break or switching the direction for growth. Leukemia inhibitory factor (LIF) is one of the interleukin-6 (IL-6) cytokine family members with the function of supporting mouse embryonic stem cells for self-renewal growth. By binding to its cognate receptor LIF receptor (LIFR), LIF activates the Janus kinase/signal transducer and activator of transcription 3 (JAK-STAT3) signaling pathway leading to the defined genes for expression in order to maintain the self-renewal growth. However, LIF also activates the glycogen synthase kinase 3 (GSK3) or mitogen-activated protein kinase (MAPK) signaling pathway for differentiation growth.
The recent work done by Drs. WANG Xiong-jun and QIAO Yunbo from the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences revealed that different regions of LIFR play different roles in the JAK-STAT3 pathway activation. These new findings were published in the recent issue of Cell Reports on Jan. 24, 2017.
The researchers found that LIFR cytoplasmic domain bears two regions with opposite roles in the JAK-STAT3 pathway activation: the juxtamembrane region is acetylated by CREB-binding protein (CBP)/p300 for the JAK-STAT3 pathway activation whereas the C-terminal region is serine-phosphorylated by MAPK to inhibit the JAK-STAT3 pathway activation. Thus, the output of LIF on stem cells largely depends on the consequence of LIFR acetylation and/or serine-phosphorylation.
Acetylated LIFR can form homo-dimer followed by recruitment of another receptor partner gp130 in order to reach a maximum activation of the JAK-STAT3 pathway. In contrast, LIFR serine-phosphorylation blocks LIFR homodimerization and serine phosphorylated LIFR fails to recruit gp130.
For a long time, four defined factors have been considered for their importance in self-renewal growth maintaining. Unexpectedly, WANG and QIAO's work strongly supports such a notion that the cytokine storm rather than the defined factor storm induction by LIF is responsible for the self-renewal growth in mouse embryonic stem cells.
This work shows a strength of a close collaboration among the labs of Dr. LI Jinsong , JING Naihe, Joe Z. HOU, and Eugene CHIN.