Biomedical Engineering Reference
In-Depth Information
In the next section, we describe the signaling pathways and related
molecules that have essential roles in cardiac development.
Table 2b.1
Effectofthemajorsignalingpathwayoncardiacspecification,
differentiation, and development
Activin/
Nodal
Canonical
Wnt
Noncanonical
Wnt
BMP
FGFs
Mesoderm
formation
-, +
+
+
Cardiac
specification
+
+
-
+
-, +
Cardiac
differentiation
+
-
+
2b.2
The TGFβ Superfamily in Cardiac
Differentiation
Bone morphogenetic protein (BMP), activin, and nodal belong to
theTGFβsuperfamiliyandregulatevariousbiologicalprocesses
such as cell proliferation, motility, differentiation, and homeostasis.
BMP, activin, and nodal bind to type I and II receptors that are
transmembrane serine/threonine kinases (Fig. 2b.2). Seven type I
andfivetypeIIreceptorshavebeenreportedinthehumangenome.
Ligand binding to the extracellular domain of a type II receptor
results in phosphorylation of the intracellular Gly-Ser region of the
type I receptor. The type I receptor is activated by phosphorylation
and subsequently phosphorylates a C-terminal SXS motif serine
residue and initiates receptor-activated Smad (R-Smad) that acts
as the intracellular signaling molecule. BMP binding to the type II
receptor results in activation of Smad1, Smad5, and Smad8, whereas
activin/nodal signaling activates Smad2 and Smad3. Phosphorylated
R-Smad binds to common-Smad (Co-Smad) and Smad4, forming an
Smad complex that translocates from the cytoplasm to the nucleus.
The Smad complex binds to Smad-binding elements (SBEs) and
regulates target gene expression, together with other transcription
factors or coactivators. Inhibitor-Smad (I-Smad), previously reported
as Smad6 and Smad7, prevents complex formation between R-Smad
and Co-Smad. Besides the Smad-mediated signaling pathway, a
non-Smad pathway independent of Smad molecules is involved in
