Role of PDGFs in cell migration
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, 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-BB, PDGF-CC and
PDGFs regulate biological functions in cells through
binding to specific Platelet-derived growth factor receptor, alpha and beta
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-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 .
All types of PDGF and
PDGF-receptors may participate in cellular migration of
different cell types , , ,
although PDGF-BB is generally a stronger
inducer this process than PDGF-AA.
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
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
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 PAKs 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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