Cytoskeleton remodeling Role of PDGFs in cell migration
Role of PDGFs in cell migration 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. Upon ligand binding, PDGF-R-alpha andPDGF-R-beta dimerize and autophosphorylate on a number of tyrosine residues.Tyrosine phosphorylated sites are used by PDGF-receptor as anchor sites forvarious SH2 domain-containing proteins. 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 . All types of PDGF and PDGF-receptors may participate in cellularmigration of different cell types , , , although PDGF -BB is generally a stronger inducer this process thanPDGF -AA. Directed cell migration is a critical feature of several physiological andpathological processes, including development, wound healing, atherosclerosis, immunity,angiogenesis, and metastasis. The migratory response involves actin cytoskeletonreorganization, polarization, cell adhesion and detachment . PDGF-receptor affect the actin cytoskeleton and cell migration through thePhosphoinositide-3-kinase, regulatory ( PI3K reg class IA ) and the catalytic (PI3K cat class IA ) subunits. These subunits activate the small G-proteins of theRho family (Cell division cycle 42 ( Cdc42 ), Ras-related C3 botulinum toxinsubstrate 1 ( Rac1 ) and Ras homolog gene family, member A ( RhoA )) . PI3K reg class IA activates PI3K cat class IA, which in turn convertsinositol 4,5-biphosphate ( PtdIns(4,5)P2 ) into inositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3 ). PtdIns(3,4,5)P3 stimulates Rac1 and RhoAthrough guanine nucleotide exchange factors (GEFs) (e.g., Vav 2 guanine nucleotideexchange factor ( VAV-2 )) ,  or T-cell lymphomainvasion and metastasis 1 ( Tiam1 ) ) Rac1 induces the formation of lamellipodia through ADP-ribosylation factorinteracting protein 2 ( POR1) and/or via p21 protein (Cdc42/Rac)-activated kinase1 ( PAK1 ) activation. Rho A induces formation of actin stressfibers and also controls cell polarization as well as cell adhesion . In addition, PI3K reg class IA may stimulate of Cdc42 activation throughGEFs such as Vav 2 guanine nucleotide exchange factor ( VAV-1 ) . ActivatedCdc42 controls the formation of filopodia through some PAK s andWiskott-Aldrich syndrome-like ( N-WASP ) activation. In fact, RhoA induces a formation of focal adhesions, and Rac1/CDC42 induce the formation of peripheral focal contacts . The downstream effector of CDC42, PAK1 may contribute to thePDGF -induced disassembly of actin stress fibers and adhesion complexes. In thiscase, PAK1 inhibits one of the GEFs of CDC42 - Neuroepithelial celltransforming 1 ( NET1 ) . Induction of this pathway contributesto PDGF -induced cell migration on collagen and links cell-surface receptors toactin cytoskeletal dynamics and cell motility, which are required for physiologicalmigration and metastatic spread of tumor cells .