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PDGF receptor signaling networks in normal and cancer cells

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Abstract

For about four decades, platelet-derived growth factors (PDGF) and their receptors have been the subject of intense research, revealing their roles in embryo development and human diseases. Drugs such as imatinib, which selectively inhibit the tyrosine kinase activity of these receptors, have been approved for the treatment of cancers such as gastrointestinal stromal tumors and chronic eosinophilic leukemia. Today, the interest in these factors is still increasing in relationship with new potential clinical applications in cancer, stroke, fibrosis and infectious diseases. This review focuses on the mechanisms of PDGF receptor signaling, with an emphasis on pathways that are important for disease development. Of particular interest, recent studies revealed significant differences between normal and cancer cells regarding signal transduction by these growth factors.

Introduction

Platelet-derived growth factor (PDGF) was identified in the seventies as a serum protein that stimulates the growth and migration of fibroblasts, vascular smooth muscle cells and glial cells [1], [2], [3]. Protein purification and cDNA cloning revealed the existence of several PDGF isoforms, one of them (PDGF-B) being equivalent to the v-SIS oncogene of simian sarcoma virus [4]. This was the first demonstration of cell transformation via an autocrine loop. Two specific membrane receptors were characterized and shown to exhibit tyrosine kinase activity [5]. The phosphorylation of cytosolic proteins on tyrosines was early recognized as a critical event in PDGF receptor signal transduction [6]. A large number of studies have progressively revealed the complexity of the PDGF signaling network.

Gene-targeting experiments in mice showed that these receptors played a key role in embryo development. In parallel, they were found mutated in different types of relatively rare tumors and leukemias. During the last decade, clinical trials indicated that drugs such as imatinib, which blocks the PDGF receptor kinase activity, can effectively treat human cancers associated with constitutive PDGF receptor activation, with the notable exception of brain tumors [7]. Several laboratories are now trying to decipher the role of PDGF in tumor stroma, angiogenesis, human fibrotic diseases and stoke, opening new possibilities of therapeutic interventions [7], [8]. Research on PDGF has led to new paradigms in embryo development [8], in oncology [7], as well as in signal transduction. The present review will focus on PDGF receptor signaling networks in normal and cancer cells.

Section snippets

Ligands and receptors

PDGFs are encoded by four different genes: PDGF-A, -B, -C and -D, which are related to VEGF and belong to the “cystine knots” protein superfamily [9]. The PDGF genes likely evolved from VEGF ancestors present in Caenorhabditis elegans and Drosophila. PDGFs are secreted as homodimeric proteins linked by two cysteine bridges. In addition, one heterodimer has been isolated: PDGF-AB (Fig. 1). PDGF-BB possesses a C-terminal basic retention motif, which binds to extracellular matrix components. The

Physiological functions of PDGF

PDGF stimulates cell proliferation and migration in a number of physiological processes, as detailed in the comprehensive review of Andrae et al. [8]. Mice deficient in PDGF ligands and receptors have revealed the critical roles of PDGF in embryo development. Mice lacking PDGF-B or PDGFRβ have a similar phenotype and die shortly after birth: they are severely deficient in vascular smooth muscle cells, such as vessel pericytes and mesiangial cells of kidney glomeruli [21]. The comparison of mice

PDGF receptor activation in diseases

PDGF ligands and receptors are proto-oncogenes that can be activated by various types of genetic alterations in cancer cells (for comprehensive reviews, see Refs. [7], [8], [28], [29]). Consistently with the expression pattern of PDGF receptors, these alterations are found in tumors of mesenchymal and glial origin, i.e. sarcoma and glioma. The v-SIS oncogene of simian sarcoma virus is highly related to PDGF-B [4]. This ligand can also be massively secreted as a result from a chromosomal

Receptor activation and early signaling

PDGFs are secreted as disulphide-bridged dimeric proteins, which interact with two receptor molecules. The crystal structure of the PDGF receptor has not been solved yet. The proposed model of receptor activation is based on the structure of other similar receptors and on mutational analysis. The extracellular domains of the receptors consist of five immunoglobulin-like domains (Fig. 1). The three first domains are binding to the ligand, while the fourth one mediates direct interactions between

Role of additional protein tyrosine kinases

PDGF receptors phosphorylate and increase the catalytic activity of several non-receptor type protein tyrosine kinases of the SRC, ABL, JAK and FER families (Fig. 4). The role of JAK kinases will be discussed below in a separate section on STAT transcription factors. The kinases that have been the most intensively studied in the context of PDGF signaling are SRC-family kinases, which are recruited to a phosphorylated residue of the receptor juxtamembrane domain (PDGFRβ-Tyr579, Fig. 3). Mutation

Phosphatidylinositol-3 kinase pathway

The p85 regulatory subunit of phosphatidylinositol-3 kinase (PI3K) binds directly to two phosphorylated tyrosine residues that are conserved in both PDGF receptors (Tyr740 and Tyr751 in PDGFRβ, Fig. 3). The formation of this complex results in the membrane translocation and increased catalytic activity of the p110 catalytic subunit, which produces phosphatidylinositol-3,4,5-triphosphate (PIP3). By a mechanism that has been extensively studied (for a review, see Ref. [69]), this lipid second

MAP kinase pathways

It was early recognized that PDGF receptors trigger the activation of the MAP kinase cascade as part of the mitogenic program. It is now clear that several proteins associated with PDGF receptors contribute to the activation of the small GTPase RAS, which leads to the sequential activation of RAF, MEK, ERK1 and ERK2 (Fig. 3). Inactive GDP-bound RAS is reloaded with GTP by the nucleotide exchange factor SOS1. This occurs when SOS1 is targeted to the plasma membrane by the adaptor protein GRB2,

Phospholipase C, calcium and PKC

Phospholipase Cγ (PLCγ) comprises two SH2 domains, which bind to two phosphorylated tyrosines located in the C-terminal part of both PDGF receptors [70]. The PH domain of PLCγ binds to PIP3 produced by PI3K. In addition, PLCγ becomes phosphorylated, which enhances its catalytic activity. PDGF is capable of activating the ubiquitous PLCγ1 and the hematopoietic PLCγ2 isoforms.

This enzyme is thus translocated in the vicinity of its substrate, phosphatidylinositol-4,5-bisphosphate, the hydrolysis

Small GTPases of the Rho family and reactive oxygen species (ROS)

The small GTPases Rac1, Cdc42 and Rho are involved in PDGF receptors-induced cell movements. They participate in the formation of leading edge structures, like lamillopedia, filopodia and actin stress fibers. These GTPases are activated by guanine nucleotide exchange factors (GEF). PDGF activates two GEFs in a SRC-dependent manner: DOCK1 in glioma and VAV2 in different cell types [65]. VAV2 is recruited to PDGFRβ via NCK adaptors, which binds directly to phosphorylated receptor tyrosines or to

JAK – STAT pathway

JAK kinases were shown to associate with PDGF receptors in a ligand-dependent manner [116], [117], [118] and PDGF induces a transient phosphorylation of the three ubiquitously expressed Janus kinases, namely JAK1, JAK2 and TYK2, and of their substrates, the signal transducers and activators of transcription STAT1, STAT3, STAT5 and STAT6 [116], [118], [119]. So far, the analysis of knock-out mice did not reveal any role of JAKs or STATs in the physiological functions of PDGF in vivo. By

Spatiotemporal regulation of PDGF receptors in cells

PDGF receptors are classical type I transmembrane proteins that are synthesized in the endoplasmic reticulum and heavily N- and O-glycosylated in the Golgi. At the plasma membrane, PDGF receptors have been found in different structures such as lipid rafts, caveolae and clathrin-coated pits. In these structures, PDGF receptors interact with membrane proteins such as lipoprotein receptor-related protein 1 (LRP1) or ephrin-B2 [132], [133]. Several studies suggested that the localization of PDGF

Conclusion and perspectives

Signaling by wild-type PDGF receptors has been extensively studied in cell culture and in mice, revealing the exquisite complexity of their signaling network. By contrast, we are only beginning to understand the differences between wild-type and oncogenic PDGF signaling. This delay is partially due to the relatively late discovery of PDGFR activating point mutations in multiple cancer types. Deciphering oncogenic PDGF signaling is critical for the development of novel rationale therapies based

Conflict of interest

The authors declare no conflict of interest.

Acknowledgements

Research on PDGF in Jean-Baptiste Demoulin's laboratory is supported by grants from the Salus Sanguinis Foundation, the Louvain Foundation and Actions de Recherche concertée (Belgium).

Jean-Baptiste Demoulin, pharmacist, PhD, is professor of molecular biology at the University of Louvain and group leader at the de Duve Institute (Brussels, Belgium). He obtained a PhD degree following his work on signal transduction by interleukin-9 at the Ludwig Institute for Cancer Research (Brussels branch) in 1999. He then moved to Uppsala University (Sweden) to study PDGF receptor signaling with Professors Carl-Henrik Heldin and Lars Rönnstrand. In 2003, he obtained an associate professor

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    Jean-Baptiste Demoulin, pharmacist, PhD, is professor of molecular biology at the University of Louvain and group leader at the de Duve Institute (Brussels, Belgium). He obtained a PhD degree following his work on signal transduction by interleukin-9 at the Ludwig Institute for Cancer Research (Brussels branch) in 1999. He then moved to Uppsala University (Sweden) to study PDGF receptor signaling with Professors Carl-Henrik Heldin and Lars Rönnstrand. In 2003, he obtained an associate professor position at the University of Louvain. His major research interests are signal transduction and gene regulation by growth factor receptors such as PDGF receptors. In particular, his group focuses on the mechanisms of cell transformation by various oncogenic mutants of these receptors.

    Ahmed Essaghir, PhD, is a senior scientist at the de Duve Institute, University of Louvain (Brussels, Belgium). He obtained master degrees in veterinary sciences (IAV Hassan II, Rabat, Morocco), in biological sciences (FUSAGx, Gembloux, Belgium) and in bioinformatics (FUSAGx and University of Brussels, Belgium). He then studied gene regulation by PDGF receptors with Professor Jean-Baptiste Demoulin (University of Louvain) and is still working in this laboratory as senior researcher in applied bioinformatics. He developed TFactS, a web-based tool that predicts the regulation of transcription factors from high throughput gene expression results. He is particularly interested in signaling and gene regulation networks.

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