Pathway Map Details
Cytoskeleton remodeling_Role of PDGFs in cell migration
Object list (links open in MetaCore):
PAK1, NET1, PDGF-C, PDGF-R-alpha, Tiam 1, CDC42, POR1, PDGF-B, PtdIns(3,4,5)P3, 18.104.22.168, PDGF receptor, PAK5, PDGF-D, PAK4, PtdIns(4,5)P2, N-WASP, VAV-2, RhoA, PI3K reg class IA (p85), VAV-1, Rac1, PDGF-R-beta, PDGF-A, PI3K cat class IA
Role of PDGFs in cell migration
Platelet-derived growth factors ( PDGF s) are members of a large family of growth factors secreted by human vascular endothelial cells and fibroblasts.
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 -AA, PDGF -AB, PDGF -BB, PDGF -CC and PDGF -DD.
PDGF s regulate biological functions in cells through binding to specific Platelet-derived growth factor receptor, alpha and beta polypeptides ( PDGF-R-alpha, PDGF-R-beta ) on the cell surface. 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 domain-containing proteins. The four dimeric isoforms, PDGF -AA, PDGF -AB, 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 .
Directed cell migration is a critical feature of several physiological and pathological processes, including development, wound healing, atherosclerosis, immunity, angiogenesis, and metastasis. The migratory response involves actin cytoskeleton reorganization, polarization, cell adhesion and detachment .
PDGF-receptor affect the actin cytoskeleton and cell migration through the Phosphoinositide-3-kinase, regulatory ( PI3K reg class IA ) and the catalytic ( PI3K cat class IA ) subunits. These subunits activate the small G-proteins of the Rho family (Cell division cycle 42 ( Cdc42 ), Ras-related C3 botulinum toxin substrate 1 ( Rac1 ) and Ras homolog gene family, member A ( RhoA )) .
PI3K reg class IA activates PI3K cat class IA, which in turn converts inositol 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 RhoA through guanine nucleotide exchange factors (GEFs) (e.g., Vav 2 guanine nucleotide exchange factor ( VAV-2 )) ,  or T-cell lymphoma invasion and metastasis 1 ( Tiam1 )  )
Rac1 induces the formation of lamellipodia through ADP-ribosylation factor interacting protein 2 ( POR1) and/or via p21 protein (Cdc42/Rac)-activated kinase 1 ( PAK1 ) activation. Rho A induces formation of actin stress fibers and also controls cell polarization as well as cell adhesion .
In addition, PI3K reg class IA may stimulate of Cdc42 activation through GEFs such as Vav 2 guanine nucleotide exchange factor ( VAV-1 ) . Activated Cdc42 controls the formation of filopodia through some PAK s and Wiskott-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 the PDGF -induced disassembly of actin stress fibers and adhesion complexes. In this case, PAK1 inhibits one of the GEFs of CDC42 - Neuroepithelial cell transforming 1 ( NET1 ) . Induction of this pathway contributes to PDGF -induced cell migration on collagen and links cell-surface receptors to actin cytoskeletal dynamics and cell motility, which are required for physiological migration and metastatic spread of tumor cells .
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