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Development PDGF signaling via MAPK cascades


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Development PDGF signaling via MAPK cascades

PDGF signaling via MAPK cascades

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, Platelet-derived growthfactor alpha and beta polypeptides ( PDGF-A and PDGF-B), and two onlyrecently discovered chains, Platelet derived growth factors C and D ( PDGF-C,PDGF-D ). The four PDGF chains assemble into homo- or heterodimers viadisulphide bonds, and five different dimeric isoforms have been described so far;PDGF -AA, PDGF -AB, PDGF -BB, PDGF -CC and PDGF-DD.

PDGF s regulate biological functions in cells through binding to specificPlatelet-derived growth factor receptor, alpha and beta polypeptides ( PDGF-R-alpha,PDGF-R-beta ) on the cell surface. The four dimeric isoforms, PDGF -AA,PDGF -AB, PDGF -BB and PDGF -CC can bind to and activePDGF-R-alpha, while PDGF -BB and PDGF -DD can specifically bind toand active PDGF-R-beta. PDGF -AB, PDGF -BB and PDGF -CC canalso stimulate heterodimeric PDGF-R alpha/beta complexes [1]. Uponligand binding, PDGF-R-alpha and PDGF-R-beta dimerize and autophosphorylateon a number of tyrosine residues. Tyrosine phosphorylated sites are used byPDGF-receptor as anchor sites for various SH2 domain-containing proteins.

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

All types of PDGFs and PDGF-receptor may participate in proliferation ofdifferent cell types [3], [4], [5], [6] via Mitogen-activated protein kinases 8-10 ( JNK(MAPK8-10) ) [7] and Mitogen-activated protein kinase 1-3 ( ERK1/2 ) cascades [8].

The JNK(MAPK8-10) cascade may be activated by phosphatidylinositol 3-kinase (PI3K ) pathway [7], [9].

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 inturn converts inositol 4,5-biphosphate ( PtdIns(4,5)P2 ) into inositol3,4,5-trisphosphate ( PtdIns(3,4,5)P3 ). PtdIns(3,4,5)P3 stimulatesRas-related C3 botulinum toxin substrate 1 ( Rac1 ) through guanine nucleotideexchange factors (e.g., Vav 2 guanine nucleotide exchange factor ( VAV-2 ))[10].

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 [8].

The ERK1/2 cascade may be activated by Growth factor receptor bound 2 (Grb2 )/Son of sevenless homolog ( Sos ) pathway [7] andPhospholipase C gamma 1 ( PLC-gamma 1 ) pathway [9]. 

Sos may be recruited to the membrane by forming complexes with SHC (Srchomology 2 domain containing) transforming protein 1 ( Shc )/ Grb2/Sos or Grb2/ Sos. Activated Sos stimulates Harvey ratsarcoma viral oncogene homolog ( H-Ras ) by release of GDP [11]. Inturn, this leads to the activation ERK1/2 via v-raf-1 murine leukemia viraloncogene homolog 1 ( c-Raf-1 )/ Mitogen-activated protein kinase kinases 1 and 2 (MEK1(MAP2K1) MEK2(MAP2K2) ) pathway. In addition, c-Raf-1 may bephosphorylated via PLC gamma 1 pathway and PDGF-receptor can activatePLC-gamma 1 by phosphorylation. Activation of PLC-gamma 1 leads to thehydrolysis of PtdIns(4,5)P2, generation of diacylglycerol ( DAG ) andinositol trisphosphate ( IP3 ) [12]. DAG and IP3stimulate Protein kinases C alpha and epsilon ( PKC-alpha, PKC-epsilon ) [13] [14] and mobilize intracellularCa('2+), respectively. PKC s in turn phosphorylate c-Raf-1.

ERK1/2 cascade may be inhibited by prostacyclin. Prostacyclin(which can be synthesized after PDGF stimulation [15] ) binds to theProstaglandin I2 (prostacyclin) receptor ( Prostacyclin receptor ), on the cellsurface. Upon binding with prostacyclin, the receptor is stabilized in its activeconformation and stimulates G-protein alpha-s. G-protein alpha-s acts as asignal 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 ofcAMP in higher eukaryotes are primarily mediated by the activation of Proteinkinase, cAMP-dependent, catalytic, alpha ( PKA-cat alpha ) [16].

Activated PKA-cat alpha phosphorylates v-raf-1 murine leukemia viral oncogenehomolog 1 ( c-Raf-1 ) and blocks binding between v-Ha-ras Harvey rat sarcoma viraloncogene homolog ( H-Ras ) and c-Raf-1 and prevents participationc-Raf-1 in the activation of ERK1/2 signaling cascade [17].

Activation of the ERK1/2 cascade leads to phosphorylation of the ELK1, memberof ETS oncogene family ( Elk-1), which stimulates serum response factor (SRF ). SRF activates transcription some protein which participate inproliferation of cells [18].

In addition, it has been previously show, that Janus kinase 2 ( Jak2 )/ signaltransducer and activator of transcription ( STAT ) pathway may participate incellular proliferation by regulating the expression of immediate-early genes, such asproto-oncogene v-myc myelocytomatosis viral oncogene homolog ( c-Myc ) [19].