Biological Regulation by Protein Phosphorylation
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
protein kinases appear to phosphory-
late tyrosine as well as serine/threonine
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-
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
/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
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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