Ganong's Review of Medical Physiology, 23rd Edition

58 SECTION I Cellular & Molecular Basis of Medical Physiology
Growth factor
Receptor
Inactive
Ras
T
GDP GTP
K Grb2 SOS
Nucleus
FIGURE 2–30 One of the direct pathways by which growth
factors alter gene activity. TK, tyrosine kinase domain; Grb2, Ras activator
controller; Sos, Ras activator; Ras, product of the ras gene; MAP K,
mitogen-activated protein kinase; MAP KK, MAP kinase kinase; TF,
transcription factors. There is cross-talk between this pathway and the
cAMP pathway, as well as cross-talk with the IP 3–DAG pathway.
some have little or no cytoplasmic tail. However, they initiate
tyrosine kinase activity in the cytoplasm. In particular, they
activate the so-called Janus tyrosine kinases (JAKs) in the
cytoplasm (Figure 2–31). These in turn phosphorylate STAT
proteins. The phosphorylated STATs form homo- and heterodimers
and move to the nucleus, where they act as transcription
factors. There are four known mammalian JAKs and
seven known STATs. Interestingly, the JAK–STAT pathway can
also be activated by growth hormone and is another important
direct path from the cell surface to the nucleus. However, it
should be emphasized that both the Ras and the JAK–STAT
pathways are complex and there is cross-talk between them and
other signaling pathways discussed previously.
Finally, note that the whole subject of second messengers
and intracellular signaling has become immensely complex,
with multiple pathways and interactions. It is only possible in
a book such as this to list highlights and present general
themes that will aid the reader in understanding the rest of
physiology (see Clinical Box 2–3).
HOMEOSTASIS
Ras Ras
Cell membrane
Active
Ras
MAP K
TF
MAP KK
Altered gene activity
The actual environment of the cells of the body is the interstitial
component of the ECF. Because normal cell function
Raf
ISF
A
Cytoplasm
B
C
D
JAK
STAT
STAT
JAK
JAK
Ligand
P
P P
STAT
P P
STAT
JAK
P
Ligand
Ligand
P
FIGURE 2–31 Signal transduction via the JAK–STAT
pathway. A) Ligand binding leads to dimerization of receptor. B) Activation
and tyrosine phosphorylation of JAKs. C) JAKs phosphorylate
STATs. D) STATs dimerize and move to nucleus, where they bind to response
elements on DNA. (Modified from Takeda K, Kishimoto T, Akira S: STAT6:
Its role in interleukin 4-mediated biological functions. J Mol Med 1997;75:317.)
JAK
P
Ligand
P
JAK
JAK
STAT
P
P P
P
P
STAT
DNA
P
P
JAK
STAT
STAT
Nucleus
Receptor