DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

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SECTION I
A
(a) Unliganded
receptor
III
I
II
IV
2 EGF
(b)
I
II
III
IV
II
I
III
IV
(c)
I
II
III
IV
II
I
III
IV
GENERAL PRINCIPLES
Inactive
tyrosine
kinase
PO 4
PO 4 PO 4
PO 4
Active kinase with
SH 2 binding domains
PO 4
PO 4
PO 4
PO 4
Grb2
Scaffold
protein
Ras
GTP GDP
Raf
MEK-PO 4
Grb2
SH 2 adaptor
protein Grb2
MAPK-PO 4
B
Cytokine
Transcription
factors
PO 4 PO 4
PO 4
Gene regulation
+
Janus
kinases
SOCS
–
Stat
PO 4
Stat
PO 4
Figure 3–10. Diagram showing the mechanism of activation of a receptor tyrosine kinase and a cytokine receptor. A. Activation of
the EGF receptor. The extracellular structure of the unliganded receptor (a) contains four domains (I-IV), which rearrange significantly
upon binding two EGF molecules. (b). The conformational changes lead to activation of the cytoplasmic tyrosine kinase domains and
tyrosine phosphorylation of intracellular regions to form SH2 binding sites. (c). The adapter molecule Grb2 binds to the phosphoryated
tyrosine residues and activates the Ras-MAP kinsase cascade. B. Activation of a cytokine receptor. Binding of the cytokine causes
dimerization of the receptor and recruits the Janus Kinases (JAKs) to the cytoplasmic tails of the receptor. JAKs trans-phosphorylate
and lead to the phosphorylation of the signal transducers and activators of transcription (STATs). The phosphorylated STATS translocate
to the nucleus and regulate transcription. There are proteins termed suppressors of cytokine signaling (SOCS) that inhibit the JAK-
STAT pathway (Alexander and Hilton, 2004).