Biological Regulation by Protein Phosphorylation
667
the biological activity and subcellular loca-
tion of the phosphatase and thereby limit
access to potential substrates. Thus, one
serine/threonine phosphatase can be uti-
lized within the cell to regulate multiple
cellular events.
The PPP family of serine/threonine
phosphatases has the most members and
is responsible for more than 90% of the
serine/threonine phosphatase activity in
mammalian cells. This family includes
some of the earliest and most extensively
studied enzymes including PP1, PP2A,
and PP2B (also called calcineurin). The
principal members of the PPM family
include PP2C and pyruvate dehydrogenase
phosphatase. Although these enzymes are
unrelated to the PPP family in terms of
protein sequence, they share structural
features within their active sites and have
a common catalytic mechanism.
Compared with the serine/threonine
phosphatases, the tyrosine phosphatases
have different structural features within
their catalytic domains and use a different
molecular mechanism for catalysis. The
tyrosine phosphatases share a common
amino acid sequence within their active
site
termed
the
PTP
signature
motif
.
Although the PTPs are responsible for a
very small fraction of the overall cellular
phosphatase activity, data from the human
genome project predict over one hundred
human enzymes. These phosphatases can
be divided into three subfamilies: tyrosine-
speciFc, dual-speciFc, and low-molecular
weight phosphatases.
Some of the tyrosine-speciFc phos-
phatases have transmembrane receptor-
like structures with an intracellular cat-
alytic domain, suggesting the existence
of
receptor-linked
proteins
that
uti-
lize the dephosphorylation of tyrosine
residues for signal transduction. Other
tyrosine-speciFc phosphatases are intra-
cellular enzymes that contain SH2 do-
mains allowing them to interact with
either receptor or cytosolic protein tyrosine
kinases or localize to different subcel-
lular regions where they function. The
dual-speciFcity phosphatases include the
Cdc25 and mitogen-activated protein ki-
nase (MAPK) phosphatase families. The
Cdc25 phosphatases are highly speciFc
for adjacent phosphothreonine and phos-
photyrosine residues on cyclin-dependent
kinases. The regulated dephosphorylation
of these sites plays a crucial role in eu-
karyotic cell cycle progression. The MAPK
phosphatases regulate signal transduction
pathways that are activated by mitogens
and stress and which control cell prolifera-
tion, differentiation, and death (apoptosis).
Much has been learned about the structure
of PTPases, but many questions on their
function and physiological substrates re-
main. This is especially true for the low
molecular weight tyrosine phosphatases, a
family of enzymes whose biological func-
tion(s) remain undeFned.
4
Phosphorylation Cascades and Multisite
Phosphorylations
Protein kinase cascades represent a com-
mon underlying theme in many signal-
transduction pathways. A classical exam-
ple is the regulation of glycogenolysis in
skeletal muscle. Epinephrine binds to the
β
-adrenergic receptor, causing activation
of adenylate cyclase, an increase in cAMP
production, and an activation of cAMP-
dependent protein kinase. This enzyme
phosphorylates and activates phosphory-
lase kinase, which in turn phosphorylates
and activates glycogen phosphorylase. In
addition, cAMP-dependent protein kinase
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