The platelet derived growth factor along with the basic fibroblast growth factor belonging to the super family of growth factors plays an important role in many cellular functions like proliferation, migration and survival, an interactive crosstalk prevails between these two growth factors in an overlapping way (Pintucci et al 2005). The vascular smooth muscle cells have two distinct phenotypes the contractile and the proliferative one in both normal and pathological conditions respectively. The synthetic phenotype among these two is said to be induced by the potent PDGF isoform, PDGF-BB, which acted synchronously with the Fibroblast Growth Factor-2 (FGF2), in cell proliferation and down regulation of adaptor protein smooth muscle α-actin (SMA).This underscores the fact that the PDGF, PDGFR and FGF2 act collaboratively to downregulate the expression of SMA, as without inhibition of SMA the plasticity of VSMC is not compromised (Chen et al 2009). In vascular smooth muscle cells the FGF-2 expression is being implicated by the PDGF-BB, talking specifically about the vascular aortic smooth muscle cells induction of high molecular weight (HMW) FGF-2 is seen which accumulates in the nucleus or nucleolus while the low molecular weight FGF-2 does not do so (Pintucci G et al 2005).
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The platelet derived growth factor isoform BB is a tyrosine kinase receptor agonist and plays transactivating role in VSMCs proliferation it usually transactivates the EGF receptor (EGFR) or the FGF receptor (FGFR) to induce the VSMCs proliferation. It is an experimental fact that FGF concentration in the medium remains constant .What seems to justify the situation is that FGF is attached to the membrane via Heparan sulfate proteoglycans (HSPGs). For the detachment of the FGF from the membrane there must be an activity of biological scissors (Proteases). However decreased concentration of FGF in the membrane is indicative of the fact that there is no scissoring activity. (Rapraeger et al 1991), (Rhoads et al 2000), (Myler et al 2002), (Rauch et al 2004). Other than the release of FGF in the external environment FGF transcription is triggered by PDGF-BB (Bilato et al. 1995).Another body of evidence states that there is a translocation of exogenous FGF into the cell (Malecki et. al 2004) that increases the cellular contents of FGF. (Fig. 5a, 5b)
Fig. 5a. FGF Translocation.
Fig. 5b Transactivating activity of FGF2 and PDGF-BB.
Fig. 5a. FGF Translocation.
The translocation of Fibroblast growth Factor which results in increased FGF cellular contents of the cell, at this stage the body of evidence states regulated PDGF/PDGFR signaling by FGF concentration
Fig. 5b. Transactivating activity of FGF2 and PDGF-BB.
Transactivation of both the receptors ,the FGFR and the PDGFR is the opening event in this mechanism, FGFR basically transactivates the PDGFR now the induced PDGF would contribute to the further signaling by deactivating the adaptor protein smooth muscle alpha actin (SMA), which normally enhances the cellular plasticity and the contractile phenotype is maintained, but in the inactive form SMA would be contributing to the cell proliferation.
Role of PDGF in different metastatic and Angiogenic cascades
Normally various growth factors are explicited in neoplastic cells, some of which are frequently upregulated. The tumor vasculature depends on an interactive loop of these factors which leads to disorganized neovascularization and metastasis. The phenomenon is said to be looped, as the FGF's upregulation increases PDGFR-α and -β expression at transcription level, similarly PDGF-BB enhances the cell's response by upregulation of FGFR-1, so that's how both these factors are regulating the neoplasticity angiogenesis and metastasis. (Lars Johan. et al 2007). PDGF-BB signaling pathways also regulate neovascularization which is a well studied aspect, quiescent endothelial cells which are usually unresponsive to PDGF-BB become sensitive to it after it is being transcriptionally activated by fibroblast growth factor (FGF)-2, the transcriptional activation switches the PDGF receptor expression in activated cells with a positive feedback looping by PDGF-BB that activates the FGF-2 signaling system (Yihai et al 2008).Fig. 6
PDGF-BB also had an involvement in tumor lymphangiogenesis among several other tumor-derived growth factors; PDGF-BB upholds the basic mitogen activating protein kinase (MAPK) pathway which leads to metastasis in lymph nodes (Renhai. et al 2004). An Autocrine pool of PDGF/PDGFR is needed for a neoplastic cell's metastatic activity through some distinct pathways, like the PDGF is also pooled into the Epithilial mesenchymal transition (EMT) induced by TGF-β, this correlated activity of PDGF is autocrine in which first the RAS molecule is capacitated which modulates PI3K pathway, so a dampened PDGF signaling would constitute to defective EMT (Martin. et al 2006), (Jie. et al 2010).PDGF's involvement in EMT is accompanied by TGF-β in this crosstalk PI3K and (ERK)/ RAS are predominantly activated, the PI3K basically enhances the RAS, this enhanced regulation is both upstream and downstream of RAS (Chun-Chao et al 2009). A TGF-β independent mechanism is also suggested by Lahsnig et al 2009 which includes the involvement of a novel interleukin like EMT inducer (ILEI) protein, ILEI enhances the RAS expression. Here a link between transcriptional activity and anti apoptotic signaling of the transcription factor NFKB is seen, NFKB accomplishes its anti-apoptotic activity after being induced by PDGF transcriptionally, through RAS and PI3K pathways, so NFKB being the target, links the anti-apoptotic signaling with transcriptional machinery (Romashkova and Makarov 1999).
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The FGF transcriptionally activates the PDGF receptors which are then recruited to the membrane. FGF and PDGF trigger expression of FGFR and PDGFR respectively. There is a decrease in the number of the receptors residing in plasma membrane after consequent internalization .Therefore there is a crosstalk of the downstream proteins to switch on the expression of the receptors to sensitize the cell to the respective ligands. Ligands responsiveness depends on the population of receptors residing in the membrane.
Fig.6. Autocrine Pool between the PDGF-BB and FGF
A novel signal transducer PDGF-DD is also involved in neovascularization. It is upregulated in pathological angiogenesis. Here a novel mechanism reports the involvement of glycogen synthase kinase-3β (GSK3β), which is antiangiogenic effector in PGDF-DD targeting. PDGF-DD mediates Ser- 9 phosphorylation and Tyr-216 dephosphorylation of GSK3β, which blunts its antiangiogenic activity, so PGDF-DD can be a therapeutic target for neovascular diseases. (Anil. et al 2010).
Role of PDGF in Breast Cancer Progression
PDGF-D is found to be upregulated in invasive breast cancer cell lines, it also correlates with Notch-1 expression and increases DNA binding activity of NFKB, as impaired PDGF-D compromised NFKB activity (Ahmad et al 2010), (Wang et al 2007). Furthermore Phospholipase D is also an important member of this molecular hierarchy including PDGF-D induced NFKB's activation. Two binding sites of NFKB are critically important for transcriptional activation of PLD-1 which is further involved in carcinogenesis (Kang et al 2010).
Interplay of PDGF with Micro RNAs
Studies involving inhibition of PDGF implicates responsiveness of miRNAs towards PDGF signaling. Specifically, in case of Human multipotent mesenchymal stromal cells (MSC) Goff et al 2008 suggests interplay of miRNAs with PDGF, in gene expression and differentiation. (Goff et al 2008).
Recent studies about micro-RNA give us some novel approaches, like their involvement in EMT. miR-200 is downregulated by PDGF-D, further downstream signaling involves upregulation of ZEB1 (zinc-finger E-box binding homeobox 1) ZEB2 and Snail2 proteins. This phenomenon imparts invasiveness in prostate cancer cell lines (Kong et al 2009). An antagonistic interaction prevails between PDGF and miR200. However a reasonable upregulation of ZEB is triggered by PDGF.
PDGF induced miR-221 regulates signaling which is responsible for some specific gene expression in SMCs and cell proliferation. The impartment of a less contractile phenotype to the SMCs is transcriptionally induced by miR-221 when treated with PDGF, again some target genes are downregulated like c-Kit and p27Kip1, among these the downregulation of c-Kit is very important as it further inhibits a nuclear coactivator called Myocardin, so this gene expression along with the cell proliferation destines the less contractile phenotype for VSMCs (Davis et al 2008).
PDGF-BB controls the expression of miR-24 which imparts synthetic (proliferative) phenotype to the VSMC .PDGF-BB signaling prevails antagonistically with that of TGFbeta signaling, this induction leads to downregulation of some downstream molecules like Tribbles-like protein-3 (Trb3), along with Trb3 Smad protein's expression is also compromised, and finally this antagonism works out wit a change in synthetic phenotype from contractile. (Chan et al 2009).
PDGF's Dynamics with LRP
LRP (LDL receptor-related protein) is involved in mediating internalization and degradation of PDGFR in collaboration with Cbl, knockdown of LRP masks PDGFR from degradation by Cbl; however an intriguing observation was made by Takayama et al that ablation of LRP did not affect the rate of recycling, rather there was an increase in the degradation and endocytosis of PDGFR. Simultaneously kinase activity of PDGFR is remarkable this aspect is puzzling because internalization of the receptor might not effect the kinase activity, however despite the degradation of receptor any kinase activity depicted, gave a clue that any other kinase enzyme is involved (Takayama et al 2005).PDGFR is actively engaged in communicating the signals from extracellular environment to the cytoplasm. FSAP is involved in cleaning PDGF protein however its activity is inhibited when it gets complexes with PN-I, this hetrodimer has an enhanced affiliation for LRP and it internalizes this protein complex, if an interactive crosstalk is established between hetrodimer and LRP's, it sequesters LRP from PDGFR as a result of which PDGFR is not internalizes an stays embedded in the plasma membrane, offering a binding site to PDGF and signal transduction initiates, hence forth PDGF is protected from cleavage by FSAP and LRP is detached from PDGFR that maintains required density of the receptors on the membrane (Muhl et al 2007).
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LRP works synchronously with PDGFR to initiate PI3K dependent signaling, which is essential for maintaining vascular integrity (Zhou et al 2009). LRP is also necessary for ERK activation, so LRP works concomitantly with PDGFR, abrogated LRP blunts the activity of ERK, this aspect rules out the presumed role of ERK to be a potential candidate for kinase activity or kinase activity in LRP deficient cells (Muratoglu et al 2010).
LRP also intervenes in PDGF ligand and receptor expression triggered by TGF mediated signaling, TGF induces expression of the target genes via SMAD proteins which moves into the nucleus and switches on PDGF and PDGFR, however there is a desensitization to TGF mediated signaling , if LRP or HHM (human homologue of Maid) quench or extinguishes the signals generated by TGF (Boucher et al 2007) or in case the PDGFR is recycled back the recycling mechanisms include different inducers and ablators like there is a molecular sea-saw of PKC (protein kinase c) and TC-PTP (T-cell protein tyrosine phosphatase), the resulting ups and downs of these two proteins dictate endocytosis or recycling of PDGFR, PKC and TC-PTP work in an anti parallel manner, PTP attenuates recycling and enhances endocytosis. Conversely PKC is involved in the recycling of the receptor via Rab4a (Hellberg et al 2009).
PDGF and Dorsal Ruffle formation
PDGF shows response in dorsal ruffle formation when actin cytoskeleton is activated by mitogens activity, mAbp1 (Mammalian actin-binding protein-1) has been accused of mediating clathrin mediated endocytosis and is necessary for PDGF-mediated dorsal ruffle formation and localization. mAbp1 hampers directly with actin regulatory protein WIP (WASp-interacting protein). This interaction is critical in the dorsal ruffle formation and the SH3 domain of WIP is responsible for this concurrence (Cortesio et al 2010). In concordance with the assumption that PDGFR is involved in dorsal Ruffle formation, another protein cdc-42 interacting protein 4 (CIP4) was observed to downregulate the PDGFR which blunted ruffle formation. However knockdown of CIP4 recapacitated dorsal ruffle formation and cellular migration. This evidence strengthens the potential role of PDGFR in dorsal ruffle formation. The exact mechanism of CIP4-like proteins was revealed by its experimental deregulation, results suggest a role of CIP4-like proteins in membrane tubulation. CIP4-like proteins regulates internalization of PDGFβ receptor which in turn has an affect on PDGF-dependent activities like actin reorganization and cell migration (Toguchi et al 2010).
PDGF and Hetro nuclear Ribonucleoprotein
PDGF induced the ubiquitination and degradation of MRLC (mRNA-encoding myosin regulatory light-chain) by MIR (MRLC-interacting protein), the activity of MIR is dependent on its association with a binding partner hnRNP (heterogeneous nuclear ribonucleoprotein), protection of MRLC's degradation by MIR inhibits novel dynamics of the cell which includes wound healing, wound healing was compromised in the cell line deficient for MIR (Nagano et al 2006). Similarly PDGF has a dominant role in inhibiting the shuttling of hnRNP's from nucleus to the cytoplasm, but if there is an impaired PDGF signaling it would facilitate the trafficking of hnRNP's from the nucleus to cytoplasm, this is indicative of the fact that PDGF is involved in dual activities, one is that it strictly inhibits hnRNP's in the nuclear premises but conversely it is also involved in executing various cytoplasmic dynamics with the courtesy of hnRNPK (Van der et al 2000).
PDGF and Non invasive EMT
Another aspect of PDGF signaling is that it is involved in epithelial mesenchymal transition (EMT) but scrupulously involved in resisting cellular migration, which is an aspect of non invasive tumor in this condition this was observed that PDGF was independent without using TGFR mediated signal transduction which is a usual path. EMT was observed in both SMAD competent and deficient cells, which proves that PDGF mediated EMT is respective of TGF signaling (Ikushima et al 2008). The novel findings also show that PDGF had a role in non-invasive EMT, in this mechanism there is again no correlation between TGFβ/Smad signaling with that of PDGF. The phenomenon was confirmed in mesothelial cells by an increased SNAIL and decreased E-Cadherin expression with presence of epithelial and mesenchymal markers (Pranali et al 2010).
Therapeutic Dimensions of PDGFs
PDGF dimers are documented to portray a cell survival landscape via phosphorylation of GSK. It executes the pro-survival effect by inducing serious modifications in GSK. In a recent experimental approach Kumar et al, 2010 showed that PDGF-DD is specifically a regulator of angiogenic and apoptotic molecules like GSK3β, which is found to be upregulated in pathological angiogenic conditions. The PDGF's working mechanism is basically the phosphorylation of Ser at 9th and dephosphorylation of Tyr at 216th residues rendering the cell more viable for survival. Further more in antiangiogenic activity would critically require GSK3β, when experimented on PDGF-DD gene (Kumar et al 2010). Likewise the role of PDGF-DD reported by Kumar et al 2010, PDGF-CC is also a candidate of GSK3β's regulator and is said to have a roleplay in neuroprotection. The PDGF-CC gene infection to the cells confirm, that it's having an anti apoptotic role, this observation was made in neuronal cells of both brain and retina.sos it could play its role in treatment of neurodegenerative diseases (Tang et al 2010).
Leukemic cells display a dense PDGFR- β localization in the membrane. It was involved in the downstream activation of PKB. However treatment of leukemic cells with neutralizing antibody of PDGFBB attenuated the signal transduction. On a similar note hepatic stellate cells have a robust expression of PDGFR-β and IGFR. Both the receptors work in collaboration to induce molecular connivance. Treatment of liver cells with EGCG downregulates the expression of both receptors (Yasuda et al 2009, Yang et al 2009). Same PDGFR-β was abrogated in liver cells using a dominant negative PDGFR-β that blunted the proliferation aspect of hepatic cells. Therefore RNA interference of this receptor might play an imperative role in producing an antineoplastic effect. Multiple receptor kinase inhibitors have more pronounced effect in terms of therapy as tumorigenesis or any other molecular discrepancy is addressed in amore broader manner (Erawan et al 2004, Chen et al 2008, and Yuqing et al 2009). PDGF has a considerable role in cardiac therapy, organs when usually treated locally do not toxify other organs, so PDGF was intramyocardially administered to throw some lime light on the PDGF's involvement in cardiac therapy, the results clearly prescribes PDGF as a cardiac performance enhancer and could be good therapeutic agent for patients having Myocardiac infarction (Patrick et al 2006, Hiranmoy et al 2009). Interstitial fluid pressure is one of the hindrances faced while treating neoplastic cells. This pressure could be reduced by intervening some normal signaling mechanisms, specifically PDGF and VEGF signaling when blocked would increase vascular remodeling and decrease vascular leakiness.Specific inhibitors can be used in combinations to make this happen by targeting the kinase activity of receptors involved. (Agnieszka et al 2009). PDGF is also having a therapeutic role in osteoporosis and bone repair, bone formation and fracture healing are some aspects of PDGF. PDGF-BB and up to some extent PGF- AA could be thus vast therapeutic entities for the treatment of osteoporosis and bone malfunctions. In case of bone malfunctioning α-receptor targeting is a probable anabolic enhancer of bone metabolism in humans. (Simon et al 2009). Further more PDGF-BB has a role in wound healing, adenovirus based gene delivery system brings about a remarkable change in the bone repair mechanism, and the phenomenon was dose dependent. This depicts the potential of PDGF-BB as a regenerative agent as well as its involvement in tissue and osseointegration (Chang et al 2010).
There is an immense repercussion of PDGF on the plasticity of the cell. The PDGF transduction cascade is instrumental to the cellular remodeling. The basic framework of the cell is reoriented and restructured to dedicate the transition. The PDGF ligand triggers the expression of PDGFR and FGFR. This captivating feature of PDGF enhances the FGF signalling as thee is an enhanced migration of the newly synthesized receptor to the membrane.
There is an integration of two linear cascades in case of PDGF and TGF signalings. The Ras proteins which are hallmark features of growth factor signaling are also contributory in TGF signaling. This collaboration generates an overlapping pathway which leads to oncogenesis. Moreover a different trend is observed in TGF signaling which is TGF independent signal cascade. ILEI is the protein that converts the signal generation from ligand dependent to independent mode. This phenomenon executes the abolition of the gate keeping proteins of the membrane. The juxtapositioning of the two individual proteins of two adjacent cells is compromised. These proteins are shuttled to the cytoplasm, this abrogates cell-cell junction and results in metastatic dissemination of the cells.
PDGF is engaged in the repression of miRNA 200. This transcript is anti-neoplastic however PDGF shuts down the transcription of miRNA 200. This opens new horizons as demolition of the miRNA 200 can be mediated at transcriptional level. Taking into consideration the post transcriptional silencing, the mRNA decay is the frontline mechanism that degrades mRNA transcript. Hence those roadmaps must be sketched to address each and every key mediator actively engaged in degrading miRNA 200 and enhancing oncogenesis.
In the quest to recognize PDGF signaling, great strides have been made to comprehend how these proteins control their downstream targets. However, scores of mechanisms by which these proteins generate linear or integrated cascades remain obscure. Recent structural data supports the idea that PDGFR is a sophisticated machine with multiple signaling outputs. Misrepresentation of growth factor signalling is the most imperative prerequisite in tumor progression. PDGF signalling regulates tumor progression by a tumor cell-autonomous mechanism or through tumor-stroma interaction and has either a tumour-suppressing or tumour-promoting function depending on cellular context. Numerous cellular context-dependent factors tightly maintain the balance of PDGF signalling and contribute to the regulation of PDGF-induced cell responses.
With an addition of substantial fraction of elucidations to the pre-existing understandings of PDGF, it is now evident that an integrated network of proteins triggers the dynamics of the cell. A positive feedback regulation exists between PDFG and FGF. Both the proteins switch on the expressions of their native receptors. This intriguing interactive display unmasks an imperative perpetuation of the cascade. In order to outnumber the displaced receptors endocytosis, there is a continuous supply of the receptors to the plasma membrane to maintain the threshold value of the population of the receptors. Henceforth the responsiveness of the cell towards FGF and PDGF is ensured. This collaboration is indicative of the fact that blunting of refractoriness is essential to induce oncogenesis. Another thing that cannot be overlooked is the crosstalks of two linear transduction cascades. This integrated framework works with striking synergy during tumor development. It is necessary to revisit the existing web of proteins with reference to PDGF signaling to tailor some effective clinical outcomes.