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The STAT3-Ser/Hes3 signaling axis: an emerging regulator of endogenous regeneration and cancer growth

Steven W Poser¹, Deric M Park, Andreas Androutsellis-Theotokis

¹Department of Medicine, University of Dresden Dresden, Germany.

Frontiers in Physiology

|October 9, 2013

Abstract:

Stem cells, by definition, are able to both self-renew (give rise to more cells of their own kind) and demonstrate multipotential (the ability to differentiate into multiple cell types). To accommodate this unique dual ability, stem cells interpret signal transduction pathways in specialized ways. Notable examples include canonical and non-canonical branches of the Notch signaling pathway, with each controlling different downstream targets (e.g., Hes1 vs. Hes3) and promoting either differentiation or self-renewal. Similarly, stem cells utilize STAT3 signaling uniquely. Most mature cells studied thus far rely on tyrosine phosphorylation (STAT3-Tyr) to promote survival and growth; in contrast, STAT3-Tyr induces the differentiation of neural stem cells (NSCs). NSCs use an alternative phosphorylation site, STAT3-Ser, to regulate survival and growth, a site that is largely redundant for this function in most other cell types. STAT3-Ser regulates Hes3, and together they form a convergence point for several signals, including Notch, Tie2, and insulin receptor activation. Disregulation and manipulation of the STAT3-Ser/Hes3 signaling pathway is important in both tumorigenesis and regenerative medicine, and worthy of extensive study.

Insights

Stem cells uniquely use STAT3-Ser signaling for survival and growth, unlike most cells relying on STAT3-Tyr. This STAT3-Ser/Hes3 pathway is crucial for stem cell self-renewal and differentiation, impacting regenerative medicine and tumorigenesis.

Area of Science:

Cell Biology
Molecular Biology
Stem Cell Biology

Background:

Stem cells possess unique self-renewal and multipotency.
Signal transduction pathways are interpreted distinctively by stem cells.
Notch signaling pathways exhibit distinct branches controlling stem cell fate.

Purpose of the Study:

To elucidate the unique role of STAT3 signaling in neural stem cells (NSCs).
To investigate the STAT3-Ser/Hes3 signaling axis in stem cell regulation.
To highlight the significance of STAT3-Ser/Hes3 in tumorigenesis and regenerative medicine.

Main Methods:

Analysis of canonical and non-canonical Notch signaling branches.
Investigation of STAT3 phosphorylation sites (STAT3-Tyr vs. STAT3-Ser).
Study of STAT3-Ser regulation of Hes3 in neural stem cells.

Main Results:

STAT3-Tyr promotes differentiation in neural stem cells, contrasting with its survival role in mature cells.
STAT3-Ser is essential for neural stem cell survival and growth.
STAT3-Ser and Hes3 act as a convergence point for multiple signaling pathways.

Conclusions:

Stem cells employ specialized signaling mechanisms, including unique STAT3 phosphorylation.
The STAT3-Ser/Hes3 pathway is a critical regulator of stem cell behavior.
Understanding STAT3-Ser/Hes3 dysregulation is vital for cancer and regenerative therapies.

Read full analysis

Keywords:

Hes3 STAT3 transcription factor regenerative medicine signal transduction stem cells

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