Smads: The intracellular hubs of signalling in regulation of pluripotency and differentiation of stem cells

Ovchinnikov, Dmitry A. and Wolvetang, Ernst J. (2011). Smads: The intracellular hubs of signalling in regulation of pluripotency and differentiation of stem cells. In Craig Atwood (Ed.), Embryonic stem cells: The hormonal regulation of pluripotency and embryogenesis (pp. 191-216) Vienna, Austria: Intech Open Access.

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Author Ovchinnikov, Dmitry A.
Wolvetang, Ernst J.
Title of chapter Smads: The intracellular hubs of signalling in regulation of pluripotency and differentiation of stem cells
Title of book Embryonic stem cells: The hormonal regulation of pluripotency and embryogenesis
Place of Publication Vienna, Austria
Publisher Intech Open Access
Publication Year 2011
Sub-type Critical review of research, literature review, critical commentary
ISBN 9789533074122
9533074124
Editor Craig Atwood
Chapter number 11
Start page 191
End page 216
Total pages 26
Total chapters 34
Collection year 2012
Language eng
Formatted Abstract/Summary
Signalling by the members of one of the largest groups of peptide signalling molecules, the
transforming growth factor beta (TGFβ) superfamily, has been implicated in the regulation of
aspects of essentially all events in the life and death of an animal cell. Smad proteins are
versatile intracellular mediators of those signals, responsible for their direct transmission from
the TGFβ superfamily receptor complexes on the membrane into the nucleus, resulting in
specific changes in gene expression. Explicitly, two different Smad groups, transmitting BMP
(bone morphogenetic protein)/GDF (growth and differentiation factor) and TGFβ/activin
signals, respectively, have been shown to be involved in the maintenance of pluripotency in
the mouse and human and all other characterised vertebrate embryonic stem cells.
Smad proteins are subject to extensive post-translational modifications, which are often a
result of activation of other important cellular signalling pathways, rendering Smads
important hubs of the major signalling pathways. Signalling by the members of the TGFβ
superfamily starts with their binding to the complexes of type I and II (and in case of TGFβs
type III) receptors, resulting in phosphorylation of the type I receptor by type II, in its turn
leading to the phosphorylation of pathway-specific regulatory Smads (R-Smads). R-Smads
then enter the nucleus in complexes with the co-Smad, Smad4, and activate or repress
transcription of target genes, often after binding other transcription factors. Much of the
intracellular regulation is achieved via regulation of the levels of Smad proteins available for
signal transduction, mostly by competition for receptor binding, degradation or changes in
phosphorylation status. The latter regulation is often achieved by phosphorylation by the
kinases activated by other important signalling pathways, notably by cytokines FGF/EGF
(fibroblast and epidermal growth factors, respectively) and Wnt proteins. It was recently
discovered that some types of Smad linker phosphorylation accompany Smad activation,
and act to ensure the transient nature of activated Smad action, thus maintaining constant
sensitivity of the cell to changes in the levels of the TGFβ/BMP signal.
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Created: Wed, 09 Mar 2011, 08:39:52 EST by Associate Professor Ernst Wolvetang on behalf of Aust Institute for Bioengineering & Nanotechnology