664
Biological Regulation by Protein Phosphorylation
AGC (14:21:63)
CAMK (17:33:74)
CMGC (8:24:61)
STE (3:5:47)
tyrosine kinase like (7:13:43)
tyrosine kinase (30:30:90)
CK1 (3:5:12)
(a)
FGR
FYN
SRC
YES
BLK
HCK
LY N
LCK
(c)
ABL
CSK
FES
FRK
SRC
TEC
FAK
EPH
ALK
ROS
INSR
DDR
MUSK
TRK
ROR
FGFR
VEGFR
PDGFR
RET
TIE
AXL
MET
RYK
ACK
JAK
SYK
EGFR
PTK7
AATYK
TK_unique
(b)
Fig. 3
Dendrogram or phylogenetic tree of
protein kinases. (a) A circular tree representing
the evolutionary divergence of the eukaryotic
protein kinase groups based on the homology
within the kinase domains. Each group can be
further divided into families and in some
instances into subfamilies. For example, the
AGC group includes the cyclic
nucleotide-regulated protein kinase family, which
can be divided into the cAMP-dependent and
cGMP-dependent protein kinase subfamilies.
The numbers in parentheses in (a) represent the
number of families, subfamilies, and human
kinases in each protein kinase group. (b) The
tyrosine kinase group can be divided into 30
families, as depicted in the flat tree. (c) The src
family of tyrosine kinases contains 8 human
tyrosine kinases and their evolutionary
divergence is depicted. A comprehensive
classi±cation scheme for each protein kinase
group is available at www.kinase.com.
the receptor type. Examples of receptor ty-
rosine kinases include the EGF receptor
and the PDGF receptor. These receptors
undergo dimerization following ligand
binding. Receptor dimerization leads to ac-
tivation of the receptor tyrosine kinase and
autophosphorylation of the receptor on
multiple tyrosine residues. The phospho-
rylated tyrosine and surrounding amino
acids serve as binding sites for secondary
signal transducing proteins containing
SH2 domains, for example, Src, phospho-
lipase C-
γ
, phosphatidylinositol 3
0
kinase,
and
ras
GTPase-activating protein (GAP).
Speci±city of binding is generated by the
sequence context surrounding the individ-
ual phosphotyrosines. These newly bound
proteins link the receptor with a variety
of different signal-transduction pathways
either directly due to the activation of their
catalytic activity or indirectly by serving as
an adaptor protein to couple other signal-
transduction molecules.
Eph receptors, the largest family of re-
ceptor tyrosine kinases, are unique in that
their ligands, ephrinAs and ephrinBs, are
cell surface proteins. The interaction of
ephrins with Eph receptors on opposing
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