Platelet-derived growth factors and their receptors: Structural and functional perspectives

doi:10.1016/j.bbapap.2012.10.015

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

Volume 1834, Issue 10, October 2013, Pages 2176-2186

https://doi.org/10.1016/j.bbapap.2012.10.015 Get rights and content

Abstract

The four types of platelet-derived growth factors (PDGFs) and the two types of PDGF receptors (PDGFRs, which belong to class III receptor tyrosine kinases) have important functions in the development of connective tissue cells. Recent structural studies have revealed novel mechanisms of PDGFs in propeptide loading and receptor recognition/activation. The detailed structural understanding of PDGF–PDGFR signaling has provided a template that can aid therapeutic intervention to counteract the aberrant signaling of this normally silent pathway, especially in proliferative diseases such as cancer. This review summarizes the advances in the PDGF system with a focus on relating the structural and functional understandings, and discusses the basic aspects of PDGFs and PDGFRs, the mechanisms of activation, and the insights into the therapeutic antagonism of PDGFRs. This article is part of a Special Issue entitled: Emerging recognition and activation mechanisms of receptor tyrosine kinases.

Highlights

► Recent advances on PDGFs and their receptors PDGFRs. ► Dissection of PDGF structural/functional understandings. ► Mechanistic insights into PDGF:propeptide recognition, receptor recognition and activation. ► Perspectives on therapeutic modulation of PDGFR signaling.

Introduction

Platelet-derived growth factors (PDGFs) are a family of four cystine-knot-type growth factors (PDGF-A, -B, -C and -D) which control the growth of connective tissue cells such as fibroblasts and smooth muscle cells [1], [2]. By acting on these mesenchymal cells, PDGFs critically regulate embryonic development, especially the formation of vessels and organs (reviewed in [3]). There are two types of receptors for PDGFs, PDGFRα and PDGFRβ, which belong to the class III receptor tyrosine kinases (RTKs), and have different expression patterns and physiological roles. PDGFRα signaling controls gastrulation and the development of several organs such as lung, intestine, skin, testis, kidney, bones, and neuroprotective tissues. PDGFRβ signaling is better recognized as an essential regulator of early hematopoiesis and blood vessel formation [3]. While PDGF–PDGFR signaling plays important roles during developmental stages, the expression of both PDGFs and PDGFRs is tightly controlled in adulthood. Enhanced PDGF–PDGFR signaling, except when happening briefly during wound repair, is generally considered abnormal, and is an important feature in a number of diseases involving proliferation, including many types of cancers, inflammation, pulmonary fibrosis and restenosis, and notably atherosclerosis [4].

PDGF signaling through PDGFRs utilizes the general strategy for RTKs, which involves ligand-induced receptor dimerization, and the subsequent receptor conformational changes that are coupled to the activation of intracellular tyrosine kinase domain (reviewed in [5]). The activation of PDGFR signaling pathways is built on structural platforms of both the ligands and the receptors, which are predicted to be conserved family-wise based on the sequence similarities between different PDGF and PDGFR subtypes. However, for decades, except for a crystal structure of the PDGF-B ligand [6], detailed mechanistic and structural understanding of PDGFR recognition and activation had been hampered until the recent elucidation of the PDGF-B:PDGFRβ complex structure. Inhibiting PDGF–PDGFR signaling, especially by selectively blocking the extracellular assembly through antibodies, ligand decoy or receptor decoys, is actively pursued in anti-cancer drug development, as these ligands and receptors serve in multiple aspects of tumor progression, such as mediating tumor growth in an autocrine fashion, recruiting fibroblast-rich tumor stroma, and regulating tumor vasculature [4]. The therapeutic efforts targeting PDGF/PDGFR are well compatible with strategies that can be derived from structural templates of both ligands and receptors. This review will summarize some current structural and functional understandings of the four PDGF ligands and the two PDGFRs.

Section snippets

The four types of PDGFs

PDGF(s) were discovered in 1970s as a platelet-dependent serum factor that stimulates the proliferation of fibroblasts, arterial smooth muscle cells, and glial cells [1], [2], [7]. There are four types of PDGF polypeptide chains as encoded by four genes. Of these four genes, PDGF-B was first characterized by amino acid sequencing to reveal its surprisingly close homology to the simian sarcoma virus oncogene v-sis [8], [9]. The cDNA of PDGF-A was subsequently cloned and its chromosomal

The propeptides of PDGFs and their association with the growth factor domains

As mentioned above, all PDGFs have pro-sequences, but PDGF-A and PDGF-B's pro-sequences contain only ~ 60 amino acids, whereas PDGF-C and PDGF-D have over 200 amino acids preceding the cysteine-knot growth factor domains. Of the long pro-sequences of PDGF-C and PDGF-D, the N-terminal part is a CUB domain which spans ~ 110 residues. A three-dimension structures of the PDGF-C/-D CUB domain is not yet available, but by analogy to known CUB domain structures [32], they should fold in a β-sandwich of

Two types of PDGFRs

The two receptors for PDGFs, PDGFRα and PDGFRβ, belong to the class III receptor tyrosine kinases (RTKs), a clan of five members including PDGFRα and PDGFRβ, KIT, FMS and FLT3 [5]. Like all RTKs, the PDGFR family of receptors have a modular architecture that utilize the extracellular domain to recognize ligands, a single transmembrane helix to pass structural/informational input from outside the cell, and an effector tyrosine kinase domain that respond to the extracellular signals, and

PDGF:PDGFR recognition

The PDGF dimer, as mentioned above, has a flat shape, with all β-strands forming a super-sheet, leaving the inter-strand loops at the ends of these strands. These loops are not only used for propeptide binding, but also for receptor binding. The binding of receptor to PDGFs is sterically incompatible with the simultaneous binding of propeptides to PDGFs. When the PDGF-A/propeptide complex and the PDGF-B/PDGFRβ complex are superimposed with the backbones of the growth factor domains overlaid, it

Recognition specificity between PDGFs and PDGFRs

PDGF-A and PDGF-B are often expressed in the same types of cells (reviewed in [64]) and the assembly of PDGF-AB heterodimers has been observed [65], [66], [67]. A study even suggested that the PDGF-AB heterodimer is preferentially formed over the homodimers [68]. There have been, however, no evidence that PDGF-C and PDGF-D form heterodimers. Therefore, considering all homodimers and heterodimers, five types of PDGF dimer proteins currently exist (Fig. 6). Given that PDGFRs are dimerized by the

Activation of PDGFRs

The activation of PDGFRs is not entirely understood mechanistically, but it likely requires receptor conformational changes in multiple steps. Initially, the bivalent nature of PDGF ligands brings two receptor protomers into proximity with one another. Importantly, activation further requires contacts between the receptor membrane-proximal regions [71], so that the intracellular kinase domains can be brought together for transphosphorylation. Although the molecular details of the interactions

Perspectives in PDGFR targeting

PDGF–PDGFR signaling plays essential roles in development, but once adulthood is reached, its function is usually detrimental rather than constructive in human physiology. An exception is in tissue repair and wound healing. PDGF-BB and PDGFRβ appear to be involved in the formational of new vessels and collagen production [77]. For this reason recombinant human PDGF-B has been used in clinical studies. However, the general need is to block PDGF–PDGFR signaling to stop or reverse proliferative

Conclusions

In the last a few years we have gained significant insight into the recognition and activation mechanisms of PDGFRs, a class of import receptor tyrosine kinase that is involved not only in physiological functions such as organogenesis and vessel formation, but also in several widespread diseases such as cancer and atherosclerosis. The significant roles of PDGFRs in cancer and vascular diseases underline the significant efforts in both academia and industry in search for specific, high-affinity,

Acknowledgements

The authors wish to thank Heli Liu and Ann Shim for comments and help in the preparation of some figures. This work in the authors’ laboratory is supported by the NIH grant 5R01GM098259.

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^☆: This article is part of a Special Issue entitled: Emerging recognition and activation mechanisms of receptor tyrosine kinases.

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ReviewPlatelet-derived growth factors and their receptors: Structural and functional perspectives☆

Abstract

Highlights

Introduction

Section snippets

The four types of PDGFs

The propeptides of PDGFs and their association with the growth factor domains

Two types of PDGFRs

PDGF:PDGFR recognition

Recognition specificity between PDGFs and PDGFRs

Activation of PDGFRs

Perspectives in PDGFR targeting

Conclusions

Acknowledgements

Exp. Cell Res.

Cytokine Growth Factor Rev.

Cell

Exp. Cell Res.

Cell

Cytokine Growth Factor Rev.

Arch. Biochem. Biophys.

J. Biol. Chem.

Structure

J. Mol. Biol.

Cell

Blood

Structure

Biochim. Biophys. Acta

Structure

Biochim. Biophys. Acta

J. Mol. Biol.

Mol. Cell

J. Biol. Chem.

J. Biol. Chem.

Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Cell

J. Biol. Chem.

Dev. Cell

Cytokine Growth Factor Rev.

Curr. Opin. Cell Biol.

Cytokine Growth Factor Rev.

A platelet-dependent serum factor that stimulates the proliferation of arterial smooth muscle cells in vitro

Proc. Natl. Acad. Sci. U. S. A.

Role of platelet-derived growth factors in physiology and medicine

Genes Dev.

Crystal structure of human platelet-derived growth factor BB

EMBO J.

Platelet-derived growth factor is structurally related to the putative transforming protein p28sis of simian sarcoma virus

Nature

Simian sarcoma virus onc gene, v-sis, is derived from the gene (or genes) encoding a platelet-derived growth factor

Science

cDNA sequence and chromosomal localization of human platelet-derived growth factor A-chain and its expression in tumour cell lines

Nature

PDGF-C is a new protease-activated ligand for the PDGF alpha-receptor

Nat. Cell Biol.

PDGF-D is a specific, protease-activated ligand for the PDGF beta-receptor

Nat. Cell Biol.

PDGF-D, a new protease-activated growth factor

Nat. Cell Biol.

Structures of a platelet-derived growth factor/propeptide complex and a platelet-derived growth factor/receptor complex

Proc. Natl. Acad. Sci. U. S. A.

Structural characterization of the human platelet-derived growth factor A-chain cDNA and gene: alternative exon usage predicts two different precursor proteins

Mol. Cell. Biol.

Defective N-sulfation of heparan sulfate proteoglycans limits PDGF-BB binding and pericyte recruitment in vascular development

Genes Dev.

Review
Platelet-derived growth factors and their receptors: Structural and functional perspectives☆