Biological Regulation by Protein Phosphorylation
663
or displacing either arginine residue can
dramatically alter the kinetics of phospho-
rylation. Although amino acid sequence
is an essential determinant for substrate
recognition, higher orders of structure can
also affect phosphorylation. Conforma-
tional states that mask or expose phospho-
rylation sites can alter the phosphorylation
of the substrate protein. Many protein
kinases can provide additional substrate
speciFcity by engaging substrate with do-
mains outside the catalytic core, such as
SH2 (src homology 2) domains.
Protein kinases are classiFed according
to the amino acid residue they phos-
phorylate. Greater than 98% of phos-
phorylation events in eukaryotic cells oc-
cur on serine and threonine residues
(by protein–serine/threonine kinases); the
remainder occur on tyrosine residues
(by
protein
tyrosine
kinases).
A
few
protein kinases appear to phosphory-
late tyrosine as well as serine/threonine
residues
and
are
classiFed
as
dual
speciFcity protein kinases. Tyrosine ki-
nases (TK) are found only in meta-
zoans, whereas serine/threonine kinases
are conserved throughout the eukaryotes.
The lipid kinase PI3K possesses pro-
tein–serine/threonine kinase activities, in
addition to phosphorylating lipid phospho-
inositides.
Histidine–aspartate
kinases
have been identiFed in bacteria, yeast,
and plants but are not known to exist
in mammals.
By aligning the kinase domain amino
acid sequences for all the protein ki-
nases, one can develop a sequence-based
hierarchy of groups, families, and sub-
families (±ig. 3). Serine/threonine kinases
are divided into 5 groups and further di-
vided into 89 families. Tyrosine kinases,
which represent a small fraction (
15% in
humans) of the kinase superfamily, con-
stitute a single group (TK) of 30 families.
This phylogenetic classiFcation of pro-
tein kinases correlates closely with general
themes of protein kinase function and reg-
ulation. ±or example, the TK group is com-
posed of tyrosine kinases only, which are
widely recognized for their roles in control-
ling cell growth and differentiation. The
group of Ca
2
+
/calmodulin-dependent pro-
tein kinases (CAMK) tend to phosphorylate
serine/threonine residues located near ba-
sic residues. Many protein kinases in this
group are activated by Ca
2
+
/calmodulin
binding to a small domain located C-
terminal to the catalytic domain.
Tyrosine kinases were identiFed Frst as
the products of viral oncogenes. These
viral protein tyrosine kinases, which we
now know are structural variants of nor-
mal cytoplasmic protein tyrosine kinases,
have unregulated tyrosine kinase activity
and thereby induce the malignant trans-
formation of cells. Their normal cellular
homologs are under stringent regula-
tory control and play critical roles in
cell growth and metabolism. Another im-
portant example of cytosolic nonreceptor
tyrosine kinases is the Janus (JAK) ki-
nase family. The JAKs are involved in
signal transduction of the cytokine recep-
tor superfamily. JAKs bind to cytoplasmic
domains on cytokine receptors and be-
come activated when the receptor binds its
ligand. The activated JAK phosphorylates
the receptor and intracellular proteins such
as STATs. Once phosphorylated, STATs
translocate to the nucleus where they reg-
ulate gene expression.
Some tyrosine kinases are cell sur-
face receptors that contain an intrinsic
tyrosine–protein kinase within their cyto-
plasmic domains. These receptor tyrosine
kinases constitute a signiFcant portion
of the TK group. Of the 90 protein ty-
rosine kinases found in humans, 58 are
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