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BMP AND WNT: AN INTRODUCTION
TO SIGNALING IN DEVELOPMENT
Once an organism develops more than one cell, the
cells need ways to communicate with one another. In mul-
ticellular organisms several key molecular signals have
evolved. These signals are frequently proteins that are
released from one cell and bind to receptors on adjacent
cells. This binding of the factor and receptor causes a
change in the cell that is mediated through a series of
intracellular transducing molecules known as the signal
transduction cascade. Changes in the molecules of the
signal transduction cascade ultimately cause changes
in gene expression. Although at first there may seem to
be a bewildering number of signals and receptors
described in this topic, there are really under 10 different
basic types of signaling systems used for nearly all of
the cell-cell interactions in development. We assume that
the reader has a basic understanding of these signaling
systems, some of the most critical signaling systems will
be highlighted in various chapters.
BMPs are members of a very large family of proteins,
known as the TGF-beta family of factors, since the first
protein of this group discovered was Transforming
Growth Factor-beta. These proteins range in size from 10
kD to 30 kD and have a characteristic structure, known
as the cystein-knot. They bind to a receptor that is a
heterodimer, composed of two type I receptor subunits
and two type II receptor subunits. The type II receptor
subunits are kinases ; that is, they can add a phosphate
group (phosphorylation) onto specific serine or threonine
amino acids on the adjacent type I receptor subunit pro-
teins. The phosphorylation of the serine or threonines
on the type I receptors causes the further phospho-
rylation of another group of proteins, known as R-smads .
The phosphorylated R-Smads then form complexes
with closely related co-Smads. This complex moves to
the cell's nucleus and binds to specific sequences in
the cell's DNA and activates nearby genes. The specific
DNA sequences are known as BMP response elements ,
and they occur in the promoter regions of genes that
are expressed when this pathway is activated by the
BMP.
Another signaling protein critical in the regulation of
development is the wnt pathway. The name wnt comes
from the rather circuitous route that led to the discovery
of this class of proteins. In the 1980s, it was discovered
that a gene necessary for wing development in flies (the
Wingless gene) and a gene that was activated in certain
forms of cancer caused by viral integration (Int-1) were
homologs. The contraction of wingless and Int, led to the
name wnt. It has turned out that there are many of these
wnt proteins in vertebrates; in humans there are 16
members of this protein family.
Wnts are secreted molecules, but they are typically
associated with the cell membrane and diffuse only
limited distances from the cell that secretes them. The wnt
proteins bind to a receptor called frizzled, an integral
membrane protein, with seven transmembrane domains.
Along with the frizzled receptor, there is a second com-
ponent to the receptor complex, the LRP protein. When
wnt is bound to its receptor complex, an intracellular
protein, b-catenin, associates with several other proteins,
including Axin, GSK3 b, and APC. This complex is con-
tinually degraded, and so exists only transiently in the
DKK
Cer1
frzB
wnt
LRP
Cell membrane
Dsh
P
b -catenin
APC
GSK
b
axin
wnt:
catenin
to nucleus
b -catenin
Nucleus
b -catenin
Transcription
TCF/LEF
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