PDGF-induced anti-apoptosis and proliferation of cells via STAT and
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, PDGF-A and
PDGF-B, and two only recently discovered chains, PDGF-C and
PDGF-D. The four PDGF chains assemble into disulphide-bonded
dimers via homo- or heterodimerization.
PDGFs regulate biological functions in cells through
binding to specific structurally related high-affinity receptors
(PDGFR) on cell surface, denoted PDGFR alpha and beta. Upon
ligand binding, the PDGFR dimerizes and autophosphorylates
on a number of tyrosine residues. Tyrosine phosphorylated sites are used by
PDGFR as anchor sites for various SH2 domain-containing
PDGF is a principal survival factor that inhibits
apoptosis and promotes proliferation. The mechanisms of cellular 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
It is show, that PDGF-B ,  and sometimes PDGF-A  regulate of
cell growth and survival via the Signal transducer and activator of transcription
(STAT) pathway 
and/or of through Nuclear factors of kappa light polypeptide in B-cells
PDGFR-beta and, to a lesser degree,
PDGFR-alpha participate in these processes .
Activated PDGFRs directly
,  or indirectly (via activate members of the Janus kinase
family (JAK) including JAK1/JAK2 and/or Tyrosine kinase 2
(TYK2) , , .
JAK1/JAK2 or TYK2 signaling
then lead to the stimulation of members of the STAT family
STAT6). However, STAT3 may also
be stimulated by the proto-oncogene tyrosine-protein kinase
(c-Src) and the Double-stranded RNA-activated protein kinase
(PKR). PKR is pre-associated
with STAT3 and PDGFR-beta. It
may facilitate tyrosine phosphorylation of STAT3 by
Activated STATs participate in the survival and
development of cells by regulating the expression of several genes such as proto-oncogene
proteins c-Fos and c-Myc , .
Upon PDGF stimulation,
PDGFRs activate Phosphatidylinositol 3-kinase
(PI3K) directly or indirectly (via Src homology 2 domain
containing transforming protein (Shc)/ Factor receptor
bound 2 (Grb2). The PI3K
regulatory subunit (PI3K reg 1A) stimulates activity of
PI3K catalytic subunits
(PI3K cat 1A), which in turn catalyzes of
PtdIns(3,4,5)P3 binds to the pleckstrin-homology domain of
serine/threonine protein kinase Akt, to recruit
Akt to the plasma membrane. When
Akt transiently associates with Inhibitor of nuclear factor
kappa B kinase catalytic subunits (IKK), it phosphorilates
and activates IKK. IKK
phosphorylates and markes for degradation of NF-KB inhibitor
(I-KB), thereby inducing NF-kB
However, under certain circumstances, Akt can activate
NF-KB through a mechanism that does not involve
I-KB degradation by modulating the transcriptional potential
of transcription factor p65 (RelA). RelA
is a component of NF-KB complex .
NF-KB regulates transcription of
c-Myc. c-Myc is a central regulator of cell
growth, death and differentiation. c-Myc is required for
cell proliferation but, in the absence of survival factors, it induces apoptosis. Thus,
PDGF stimulates c-Myc-mediated
proliferation by activating the
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The PDGF family: four gene products form five dimeric isoforms.
Cytokine & growth factor reviews 2004 Aug;15(4):197-204
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NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling.
Nature 1999 Sep 2;401(6748):86-90
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Cytosolic phospholipase A2 is an effector of Jak/STAT signaling and is involved in platelet-derived growth factor BB-induced growth in vascular smooth muscle cells.
The Journal of biological chemistry 2003 Mar 14;278(11):9986-92
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An essential role of the Jak-2/STAT-3/cytosolic phospholipase A(2) axis in platelet-derived growth factor BB-induced vascular smooth muscle cell motility.
The Journal of biological chemistry 2004 Oct 29;279(44):46122-8
- Dell'Albani P, Kahn MA, Cole R, Condorelli DF, Giuffrida-Stella AM, de Vellis J
Oligodendroglial survival factors, PDGF-AA and CNTF, activate similar JAK/STAT signaling pathways.
Journal of neuroscience research 1998 Oct 15;54(2):191-205
- Shen Y, Devgan G, Darnell JE Jr, Bromberg JF
Constitutively activated Stat3 protects fibroblasts from serum withdrawal and UV-induced apoptosis and antagonizes the proapoptotic effects of activated Stat1.
Proceedings of the National Academy of Sciences of the United States of America 2001 Feb 13;98(4):1543-8
- Valgeirsdottir S, Paukku K, Silvennoinen O, Heldin CH, Claesson-Welsh L
Activation of Stat5 by platelet-derived growth factor (PDGF) is dependent on phosphorylation sites in PDGF beta-receptor juxtamembrane and kinase insert domains.
Oncogene 1998 Jan 29;16(4):505-15
- Vignais ML, Sadowski HB, Watling D, Rogers NC, Gilman M
Platelet-derived growth factor induces phosphorylation of multiple JAK family kinases and STAT proteins.
Molecular and cellular biology 1996 Apr;16(4):1759-69
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Platelet-derived growth factor (PDGF)-induced activation of signal transducer and activator of transcription (Stat) 5 is mediated by PDGF beta-receptor and is not dependent on c-src, fyn, jak1 or jak2 kinases.
The Biochemical journal 2000 Feb 1;345 Pt 3:759-66
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Stat6 and Jak1 are common elements in platelet-derived growth factor and interleukin-4 signal transduction pathways in NIH 3T3 fibroblasts.
The Journal of biological chemistry 1996 Sep 6;271(36):22175-82
- Choudhury GG, Marra F, Kiyomoto H, Abboud HE
PDGF stimulates tyrosine phosphorylation of JAK 1 protein tyrosine kinase in human mesangial cells.
Kidney international 1996 Jan;49(1):19-25
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Distinct mechanisms of activation of Stat1 and Stat3 by platelet-derived growth factor receptor in a cell-free system.
Molecular and cellular biology 1999 May;19(5):3727-35
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Protein kinase PKR is required for platelet-derived growth factor signaling of c-fos gene expression via Erks and Stat3.
The EMBO journal 2001 May 15;20(10):2487-96
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Role of the JAK-STAT pathway in PDGF-stimulated proliferation of human airway smooth muscle cells.
American journal of physiology. Lung cellular and molecular physiology 2002 Jun;282(6):L1296-304