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Development PDGF signaling via STATs and NF-kB

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Development PDGF signaling via STATs and NF-kB

PDGF-induced anti-apoptosis and proliferation of cells via STAT and NF-KBpathways

Platelet-derived growth factors ( PDGF s) are members of a large family ofgrowth factors secreted by human vascular endothelial cells and fibroblasts.

The PDGF family is composed of four different polypeptide chains encoded byfour different genes. There are two classical PDGF chains, PDGF-A andPDGF-B, and two only recently discovered chains, PDGF-C and PDGF-D. The fourPDGF chains assemble into disulphide-bonded dimers via homo- orheterodimerization.

PDGF s regulate biological functions in cells through binding to specificstructurally related high-affinity receptors ( PDGFR ) on cell surface, denotedPDGFR alpha and beta. Upon ligand binding, the PDGFR dimerizes andautophosphorylates on a number of tyrosine residues. Tyrosine phosphorylated sites areused by PDGFR as anchor sites for various SH2 domain-containing proteins [1].

PDGF is a principal survival factor that inhibits apoptosis and promotesproliferation. The mechanisms of cellular proliferation and transformation areintrinsically linked to the process of apoptosis: the default of proliferating cells isto undergo apoptosis unless specific survival signals are provided [2].

It is show, that PDGF-B [3], [4] and sometimesPDGF-A [5] regulate of cell growth and survival via the Signaltransducer and activator of transcription ( STAT ) pathway [6] and/orof through Nuclear factors of kappa light polypeptide in B-cells ( NF-KB) [2]. PDGFR -beta and, to a lesser degree, PDGFR -alpha participate inthese processes [7].

Activated PDGFR s directly [8], [9] or indirectly (viaactivate members of the Janus kinase family (JAK) including JAK1/JAK2 and/orTyrosine kinase 2 ( TYK2 ) [10], [10], [11]. JAK1/JAK2 orTYK2 signaling then lead to the stimulation of members of the STAT family (STAT1, STAT3, STAT5, STAT6 ). However, STAT3 mayalso be stimulated by the proto-oncogene tyrosine-protein kinase ( c-Src ) and theDouble-stranded RNA-activated protein kinase ( PKR ). PKR is pre-associatedwith STAT3 and PDGFR -beta. It may facilitate tyrosine phosphorylation ofSTAT3 by c-Src [12].

Activated STAT s participate in the survival and development of cells byregulating the expression of several genes such as proto-oncogene proteins c-Fosand c-Myc [12], [13].

Upon PDGF stimulation, PDGFRs activate Phosphatidylinositol 3-kinase (PI3K ) directly or indirectly (via Src homology 2 domain containing transformingprotein ( Shc )/ Factor receptor bound 2 ( Grb2 ). The PI3Kregulatory subunit ( PI3K reg 1A ) stimulates activity of PI3K catalyticsubunits ( PI3K cat 1A ), which in turn catalyzes of reaction conversionPhosphatidylinositol-4,5-biphosphate ( PtdIns(4,5)P2 ) intoPhosphatidylinositol-3,4,5-trisphosphate ( PtdIns(3,4,5)P3 ).PtdIns(3,4,5)P3 binds to the pleckstrin-homology domain of serine/threonineprotein kinase Akt, to recruit Akt to the plasma membrane. When Akttransiently associates with Inhibitor of nuclear factor kappa B kinase catalytic subunits( IKK ), it phosphorilates and activates IKK. IKK phosphorylatesand markes for degradation of NF-KB inhibitor ( I-KB ), thereby inducingNF-kB DNA-binding activity.

However, under certain circumstances, Akt can activate NF-KB through amechanism that does not involve I-KB degradation by modulating the transcriptionalpotential of transcription factor p65 ( RelA ). RelA is a component ofNF-KB complex [2].

NF-KB regulates transcription of c-Myc. c-Myc is a centralregulator of cell growth, death and differentiation. c-Myc is required for cellproliferation but, in the absence of survival factors, it induces apoptosis. Thus,PDGF stimulates c-Myc -mediated proliferation by activating theH-Ras/ PI3K/ Akt pathway [2].