PDGF signaling via MAPK cascades
Platelet-derived growth factors (PDGFs) are members of a
large family of growth factors secreted by human vascular endothelial cells and
The PDGF family is composed of four different polypeptide
chains encoded by four different genes. There are two classical
PDGF chains, Platelet-derived growth factor alpha and beta
polypeptides (PDGF-A and
PDGF-B), and two only recently discovered chains, Platelet
derived growth factors C and D
(PDGF-C, PDGF-D). The four
PDGF chains assemble into homo- or heterodimers via
disulphide bonds, and five different dimeric isoforms have been described so far;
PDGF-BB, PDGF-CC and
PDGFs regulate biological functions in cells through
binding to specific Platelet-derived growth factor receptor, alpha and beta
PDGF-R-beta) on the cell surface. The four dimeric isoforms,
PDGF-BB and PDGF-CC can bind to
and active PDGF-R-alpha, while
PDGF-BB and PDGF-DD can
specifically bind to and active PDGF-R-beta.
PDGF-AB, PDGF-BB and
PDGF-CC can also stimulate heterodimeric
PDGF-R alpha/beta complexes .Upon ligand
binding, PDGF-R-alpha and
PDGF-R-beta dimerize and autophosphorylate on a number of
tyrosine residues. Tyrosine phosphorylated sites are used by
PDGF-receptor as anchor sites for various SH2
PDGF is a principal survival factor that inhibits
apoptosis and promotes proliferation. The mechanisms of cell proliferation and
transformation are intrinsically linked to the process of apoptosis: the default of
proliferating cells is to undergo apoptosis unless specific survival signals are provided
All types of PDGFs and
PDGF-receptor may participate in proliferation of different
cell types , , ,  via
Mitogen-activated protein kinases 8-10 (JNK(MAPK8-10))
 and Mitogen-activated protein kinase 1-3
(ERK1/2) cascades .
The JNK(MAPK8-10) cascade may be activated by
phosphatidylinositol 3-kinase (PI3K) pathway , .
PDGF-receptor directly activates the
Phosphoinositide-3-kinase, regulatory (PI3K reg class IA)
and the catalytic (PI3K cat class IA)
subunits. PI3K reg class IA stimulates the activity of
PI3K cat class IA, which in turn converts
PtdIns(3,4,5)P3 stimulates Ras-related C3 botulinum toxin
substrate 1 (Rac1) through guanine nucleotide exchange
factors (e.g., Vav 2 guanine nucleotide exchange factor
Activated Rac1 stimulates Mitogen-activated protein
kinase kinase kinase 1 (MEKK1(MAP3K1))/ Mitogen-activated
protein kinase kinase 4 (MEK4(MAP2K4))/
JNK(MAPK8-10) pathway that leads to phosphorylation of the Jun oncogene
(c-Jun) transcription factor.
c-Jun induces activation of transcription of protein
involved in cellular proliferation .
The ERK1/2 cascade may be activated by Growth factor
receptor bound 2 (Grb2)/Son of sevenless homolog
(Sos) pathway  and Phospholipase
C gamma 1 (PLC-gamma 1) pathway
Sos may be recruited to the membrane by forming complexes
with SHC (Src homology 2 domain containing) transforming protein 1
Sos or Grb2
Sos stimulates Harvey rat sarcoma viral oncogene homolog
(H-Ras) by release of GDP . In turn, this
leads to the activation ERK1/2 via v-raf-1 murine leukemia
viral oncogene homolog 1 (c-Raf-1)/ Mitogen-activated
protein kinase kinases 1 and 2 (MEK1(MAP2K1) MEK2(MAP2K2))
pathway. In addition, c-Raf-1 may be phosphorylated
via PLC gamma 1 pathway and
activate PLC-gamma 1 by phosphorylation.
Activation of PLC-gamma 1 leads to the hydrolysis of
PtdIns(4,5)P2, generation of diacylglycerol
(DAG) and inositol trisphosphate
(IP3) . DAG and
IP3 stimulate Protein kinases C alpha and epsilon
epsilon) ,  and mobilize
intracellular Ca('2+), respectively.
PKCs in turn phosphorylate
ERK1/2 cascade may be inhibited by
(which can be synthesized after PDGF stimulation ) binds to the Prostaglandin I2 (prostacyclin) receptor
(Prostacyclin receptor), on the cell surface. Upon binding
with prostacyclin, the receptor is stabilized in its active
conformation and stimulates G-protein alpha-s.
G-protein alpha-s acts as a signal transducers for
activation of Adenylate cyclase 3 (adenylate cyclase III),
which catalyzes the reaction of synthesis adenosine 3',5'-cyclic phosphate
(cAMP) from adenosine-5'-triphosphate
(ATP). The intracellular effects of
cAMP in higher eukaryotes are primarily mediated by the
activation of Protein kinase, cAMP-dependent, catalytic, alpha (PKA-cat
Activated PKA-cat alpha phosphorylates v-raf-1 murine
leukemia viral oncogene homolog 1 (c-Raf-1) and blocks
binding between v-Ha-ras Harvey rat sarcoma viral oncogene homolog
(H-Ras) and c-Raf-1
and prevents participation
c-Raf-1 in the activation of ERK1/2 signaling
Activation of the ERK1/2 cascade leads to phosphorylation
of the ELK1, member of ETS oncogene family (Elk-1), which
stimulates serum response factor (SRF).
SRF activates transcription some protein which participate
in proliferation of cells .
In addition, it has been previously show, that Janus
kinase 2 (Jak2)/ signal
transducer and activator of transcription
(STAT) pathway may participate
in cellular proliferation by regulating the expression of immediate-early genes, such as
proto-oncogene v-myc myelocytomatosis viral oncogene homolog
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