Biological Regulation by Protein Phosphorylation
665
cells induces receptor clustering and phos-
phorylation, and subsequent recruitment
of intracellular signaling molecules. The
binding of ephrin to the Eph receptor
also initiates a functional response in
the ligand-expressing cell, although the
biochemical mechanism for this effect
is not yet clear. Such reciprocal signal-
transduction between Eph receptors and
their ligands regulate cell–cell repulsion
and adhesion mechanisms involved in
the formation and maintenance of or-
gan systems.
Several
serine/threonine-receptor
ki-
nases exist. These include lectin receptor
kinases, transforming growth factor
β
(TGF-
β
) receptors, and activin. TGF-
β
receptors (types I and II) control the devel-
opment and homeostasis of most tissues
in metazoan organisms. To exert their
s
i
gn
a
l
,t
yp
eI
Iandt
yp
eIr
e
c
ep
t
o
r
sa
c
t
in sequence. TGF-
β
±rst binds to the
type II receptor, which contains intrin-
sic kinase activity. The type I receptor
is then recruited and phosphorylated in
its intracellular domain by the type II re-
ceptor, leading to activation of its kinase
activity. Similar to JAK-STAT signaling,
activated type I TGF-
β
receptor recruits
and phosphorylates Smad proteins, which
then translocate into the nucleus where
they regulate gene transcription.
Mechanistically, many protein kinases
are regulated through autoinhibition. This
involves a pseudosubstrate domain, found
either in the primary sequence of the
kinase itself or on a separate regulatory
protein that interacts with the active site.
Activation is achieved when the autoin-
hibitory domain is displaced from the ac-
tive site. Protein serine/threonine kinases
activated by second messengers, intracel-
lular molecules that are generated in re-
sponse to extracellular signals (Fig. 4), are
kinases regulated by autoinhibition. For
these enzymes, binding of the second mes-
senger induces a conformational change
that releases the inhibitory domain. These
protein kinases are classi±ed according
to the second messenger that stimulates
their activity. These groups include pro-
tein kinases activated by cyclic nucleotides
(cAMP- and cGMP-dependent protein ki-
nases), calcium plus calmodulin (includ-
ing Ca
2
+
/calmodulin-dependent protein
kinase II and myosin light-chain kinase),
and diacylglycerol (protein kinase C). In
the protein tyrosine kinase Src, activa-
tion arises from phosphorylation-induced
conformational changes, resulting in dis-
placing part of the C-terminal tail that
otherwise occupies the active site and pre-
vents substrate from binding to enzyme.
Activation of many protein kinases, but
not all, require phosphorylation of either a
conserved threonine or tyrosine residue in
a loop structure called the activation loop
(Fig. 2). These protein kinases have low
basal activities as a result of the unphos-
phorylated form possessing low af±nity
for ATP and incorrectly positioned cat-
alytic residues. Phosphorylation induces a
structural change in the activation loop,
which results in remodeling of the active
site leading to optimized substrate binding
and catalysis.
3
Classifcation and Properties oF
Phosphoprotein Phosphatases
Traditionally, phosphoprotein phospha-
tases were categorized by their selectiv-
ity for phosphoserine/phosphothreonine
or phosphotyrosine residues and further
separated on the basis of sensitivities
to endogenous inhibitors, requirements
for cations, and
in vitro
substrate speci-
±city. More recent gene sequencing efforts
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