PDGF Pathway
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PDGF Pathway
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. Migration requires cell communication with adjacent cells and with ECM (Extracellular Matrix Components) and is triggered by a gradient of chemotactic factors, including PDGF (Platelet-Derived Growth Factor) and its receptors (Ref.1). PDGF is a member of a large family of growth factors, which includes VEGF (Vascular Endothelial Growth Factor), PlGF (Placental Growth Factor), and CTGF (Connective Tissue Growth Factor), a PDGF-like factor secreted by human vascular endothelial cells and fibroblasts. PDGFR (PDGF Receptors) are not uniformly distributed in the cell membrane, but rather concentrated in caveolae, distinct membrane invaginations which are involved in endocytosis. Ligand binding induces internalization of the ligand-PDGFR complex into the endosomes. Upon fusion of the endosomes with lysosomes the PDGFR complex is degraded. In addition to degradation in lysosomes, PDGFRs also undergo cytoplasmic degradation in proteasomes after ubiquitination (Ref.2 & 3).

PDGF is a dimeric peptide of homologous A and B-polypeptide chains, which are assembled as homodimers (PDGFAA and PDGFBB) or heterodimer (PDGFAB). PDGF regulates its biological functions on target cells through its binding to specific structurally related high-affinity receptors on cell surface, denoted Alpha and Beta. The PDGFR-Alpha binds PDGFAA and PDGFBB, whereas the PDGFR-Beta binds PDGFBB only. Upon ligand binding, the PDGFR dimerizes and autophosphorylates on a number of tyrosine residues. Tyrosine phosphorylated sites are used by PDGFR as anchor sites for various SH2 domain-containing proteins. These proteins fall into two categories: the signaling enzymes such as PLC-Gamma (Phospholipase-C-Gamma), PI3K (Phosphatidylinositol-3 Kinase), Src family members, the Ras-GAP (GTPase-activating Protein of Ras), and the tyrosine phosphatase Syp/SH-PTP2; and the adaptor molecules, including SHC (SH2 containing protein) and GRB2 (Growth Factor Receptor-Bound Protein-2) that is associated with SOS, the nucleotide exchange factor for Ras. The recruitment of the GRB2-SOS complex by the activated PDGFR allows the conversion of the inactive Ras-GDP into active Ras-GTP. Ras activation leads to the stimulation of the MAPKs (Mitogen Activated Protein Kinases) of the ERK (Extracellular Signal-Regulated Kinase) type, which occurs by sequential activation of Raf1, MEKs (MAPK/ERK kinases), MEKK1 (MAP/ERK Kinase Kinase-1) and JNKs (Jun N-terminal Kinases). Activated ERK1/2 provide a link between plasma membrane receptors and the nucleus, where they are translocated and serve as important regulators of nuclear transcriptional factors such as Elk1, c-Jun, c-Fos, SRF (Serum Response Factor) and TRE (also known as ATF2, Activating Transcription Factor-2) (Ref.4). The downstream mitogenic signaling mechanisms also include the Ca2+/Calmodulin and PKC (Protein Kinase-C)-dependent Na+/H+ exchanger. Activation of a CaCn (Calcium Channel) via Ras results in Ca2+ influx, which increases intracellular concentration of Ca2+. At the membrane SH2 (Src Homology-2) domains of PI3K, associate with its catalytic subunit and phosphorylates the membrane lipids PIP (Phosphatidylinositol-4-Phosphate) and PIP2 (Phosphatidylinositol- (4, 5)-Bisphosphate) (Ref.7). PIP2 activation by PLC-Gamma catalyzes the formation of DAG (Diacylglycerol) and IP3 (Inositol Triphosphate). In addition to its mitogenic effect, the PI3K, activate yet another kinase, the Akt Pathway, which is responsible for the survival or the anti-apoptotic arm of PDGF signaling pathways (Ref.5). Direct association between Akt and one IKK (I-KappaB Kinase) subunit, IKK-Beta that phosphorylate I-KappaB is involved in PDGF-induced activation of NF-KappaB (Nuclear Factor-KappaB) (Ref.6).

The PDGFR affect actin cytoskeleton and cell migration, through the small G-proteins of the Rho family. Rho and small G-proteins control the formation of filopodia (CDC42), lamellipodia (Rac and Por1), and actin stress fibers (RhoA) and also control cell polarization as well as cell adhesion. In fact, RhoA induces formation of focal adhesions, and Rac/CDC42 induce formation of peripheral focal contacts through PAK (p21 Activated Kinase) activation. The exchange factor TIAM1 (T-Cell Lymphoma Invasion and Metastasis-1) also regulates multiple cellular functions by activating the Rac-GTPase. The downstream effectors of CDC42 and N-WASP (Wiskott - Aldrich Syndrome Proteins) are essential not only for PDGF-induced filopodia formation, but also contribute to the PDGF-induced disassembly of actin stress fibers and adhesion complexes. 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 (Ref.1). PDGFR also use a parallel Ras-independent but Src-dependent pathway that culminates with the nuclear expression of the c-Myc proto-oncogene. Vav1 and Vav2 participate in the transduction pathway connecting the PDGFR to the c-Myc promoter. PDGFBB and two viral oncoproteins, BPV-E5 and V-Sis, bind the PDGFR-Beta to activate the JAK-STATs (Janus family of kinases-Signal Transducers and Activators of Transcription) signal transduction pathway. Nuclear STAT (STAT1 and STAT3) dimers bind to SIE (Sis-Inducible Element) in the c-Fos promoter, conferring PDGF-dependent activation of c-Fos transcription (Ref.8). Negative feedback for the mitogenic effects of PDGF is provided by cAMP (Cyclic Adenosine Monophosphate)-dependent protein kinase, which is activated by PDGF through cPLA2 (cytosolic Phospholipase-A2), activation with an increased release of Arachidonic Acid and biosynthesis of PtgI2 (Prostaglandin-I2) cascade synthesis and activation of AC (Adenyl Cyclase); the cAMP-dependent protein kinase inhibits ERK1/2 and proliferation cascades, COX2 (Cyclooxygenase-2), Phospholipids that are activated in PDGF-stimulated cells through phosphorylation (Ref.2 & 3).

PDGF is known to be produced by a number of cell types besides platelets and it has been found to be a mitogen for almost all mesenchymally-derived cells, i.e. connective tissue cells, arterial smooth muscle cells, including dermal fibroblasts, chondrocytes and some epithelial and endothelial cells. PDGF is involved in autocrine and paracrine growth stimulation of human tumors such as glioblastoma and fibrosarcoma, melanoma, breast carcinoma, lung carcinoma, glioma, esophageal carcinoma, Kaposi’s sarcoma and ovarian neoplasms. Overexpression of the normal human PDGFBB gene (c-Sis, proto-oncogene) causes generation of fibro sarcoma, chronic myelomonocytic leukemia, and vascular connective tissue stroma with no necrotic, tumorigenic and metastatic effects. Furthermore, PDGF has been implicated in the pathogenesis of several non-malignant proliferative diseases including hypertrophic scars and scleroderma of the skin, atherosclerosis (myointimal thickening of arterial walls), lung fibrosis (Hermansky-Pudlak syndrome), including bronchiolitis obliterans-organizing pneumonia, obliterative bronchiolitis after transplantation, Histiocytosis-X and coal workers pneumoconiosis, as well as fibrosis following hypoxic pulmonary hypertension, breathing of high concentrations of oxygen and exposure to asbestos. An increased amount of PDGF is also seen in bronchial lavage of lungs after acute injury, restenosis following vascular angioplasty, giant cell arteritis, liver cirrhosis, palmar fibrosis (Dupuytrens contracture), in chronic synovial inflammation, and rheumatoid arthritis. Expression of PDGFA plays a central role in regulating female reproductive tract function by increasing uterine smooth muscle cells during the physiological hypertrophy of pregnancy. PDGFBB increases the healing of decubitus ulcers in patients with decreased healing capacity, such as diabetics, but inhibit bone regeneration induced by osteogenin. Recent research has implicated PDGF as potential therapeutic agents for patients with Parkinsons disease. Thus, the accumulating evidence for the involvement of PDGF in a variety of human proliferative disorders has led to a search for specific PDGFRs and that do not inhibit other kinases (Ref.2 & 3).