Induction of c-
fos mRNA is a key step in the
regulation of cell cycle entry by mitogenic growth factors, such as
epidermal growth factor (EGF) and platelet-derived growth factor
(PDGF). Expression of c-
fos is necessary for subsequent
steps in the growth response, including G
1 progression and DNA synthesis.
1 2 3 Results from several
laboratories indicate that these growth factors, after binding their
respective receptor tyrosine kinases (RTKs), induce c-
fos transcription through the Erk1/2-signaling pathway.
4 5 6 Typically, RTK autophosphorylation leads to the activation of the small
G-protein Ras, initiating a kinase cascade consisting of Raf-1,
mitogen-activated kinase kinase (MEK)-1, and the mitogen-activated
protein (MAP) kinases, Erk1 and Erk2.
4 5 The principal
target substrate of this cascade in mammalian cells is the
transcription factor, Elk1.
7 Phosphorylated Elk1 binds the
serum response element (SRE) of the c-
fos promoter in
association with the serum response factor (SRF) dimer
6 and transactivates c-
fos transcription (see
Fig. 1 ). Several
other enzymes are also activated in response to autophosphorylation of
the RTK. These include phospholipase C (PLC)-γ and PI3-kinase, which
regulate phosphoinositide metabolism and several members of the Janus
kinase/signal transducers and activators of transcription (JAK/STAT)
family.
8 Activation of PLCγ promotes hydrolysis of the
polyphosphoinositide, phosphatidylinositol 4,5-bisphosphate
(PIP2)
4 5 to form diacylglycerol and
IP3,
1 4 5 leading to the activation of PKC. Specific
isoforms of PKC may in turn promote c-
fos transcription by
interacting with the Ras/Raf/Erk1/2 pathway or by increasing SRF
activity.
9 Activation of PI3 kinase, however, generates
polyphosphoinositides that are phosphorylated at the 3 position of the
inositol ring and are particularly important in regulating cytoskeletal
reorganization.
10 11 12 In addition, RTK-dependent
activation of JAK/STAT family members has been implicated in the
proliferative response in several cell types.
13 14 Interactions among the various pathways activated by the RTK increase
the complexity and flexibility of the cellular response and may enable
cell-type–specific responses.