Ganong's Review of Medical Physiology, 23rd Edition

58 SECTION ICellular & Molecular Basis of Medical Physiology

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 het-
erodimers and move to the nucleus, where they act as trans-
cription 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

The actual environment of the cells of the body is the intersti-
tial component of the ECF. Because normal cell function

FIGURE 2–30 One of the direct pathways by which growth
factors alter gene activity. TK, tyrosine kinase domain; Grb2, Ras acti-
vator 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.

T

K Grb2 SOS

Growth factor

Receptor

Cell membrane

Active

Ras

Inactive

Ras

GDP GTP

Raf

MAP KK

MAP K

TF

Nucleus

Altered gene activity

Ras Ras

FIGURE 2–31 Signal transduction via the JAK–STAT

pathway. A) Ligand binding leads to dimerization of receptor. B) Acti-

vation and tyrosine phosphorylation of JAKs. C) JAKs phosphorylate

STATs. D) STATs dimerize and move to nucleus, where they bind to re-

sponse 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.)

Ligand

C

JAK

STAT STAT

P

JAK

P

P P

P P

Ligand

D

JAK

P

JAK

P

P

STAT

P

STAT

P

Ligand

B

JAK

STAT

P

JAK

P

STAT

P P

Ligand

A

Cytoplasm

ISF

Receptor

JAK JAK

STAT

P

Nucleus

DNA

STAT