PDGFs and their receptors

doi:10.1016/j.gene.2017.03.003

Gene

Volume 614, 30 May 2017, Pages 1-7

https://doi.org/10.1016/j.gene.2017.03.003 Get rights and content

Highlights

•
There are multiple modes of activating PDGFRs.
•
Once activated, PDGFRs contribute to various pathological conditions.
•
The PDGF/PDGFR family constitutes largely untapped therapeutic targets.
•
The precise role of PDGFR in pathology along with receptor-specific agonists will enable the development of such therapies.

Abstract

The platelet-derived growth factor (PDGF)/PDGFR receptor (PDGFR) family is essential for a vast array of physiological processes such as migration and proliferation of percityes that contribute to the formation and proper function of blood vessels. While ligand-dependent de-repression of the PDGFR's kinase activity is the major mode by which the PDGFR is activated, there are additional mechanisms to activate PDGFRs. Deregulated PDGFR activity contributes to various pathological conditions, and hence the PDGF/PDGFR family members are viable therapeutic targets. An increased appreciation of which PDGFR contributes to pathology, biomarkers that indicate the amplitude and mode of activation, and receptor-specific antagonists are necessary for the development of next-generation therapies that target the PDGF/PDGFR family.

Section snippets

The PDGF family and their relationships

There are four platelet-derived growth factor (PDGF) genes (PDGFA, PDGFB, PDGFC and PDGFD) that reside on chromosomes 7, 22, 4 and 11 in humans, and chromosomes 5, 15, 3 and 9 in mice, respectively. Biologically active (able to activate a PDGF receptor (PDGFR)) PDGF is a dimer of two PDGF protein chains. Extracellular, proteolytic processing is required for activation of some isoforms of PDGF (PDGF-C and PDGF-D), while this step occurs intracellularly for PDGF-A, PDGF-B and PDGF-AB (Fredriksson

PDGF-mediated

The best-known mechanism to activated PDGFRs is the PDGF-mediated (direct) mode of activation (Fig. 1). PDGF assembles two PDGFR molecules and thereby intensely activates the receptor's intrinsic tyrosine kinase activity. The activated PDGFR tyrosine phosphorylates substrates and thereby engages signaling cascades that drive subsequent cellular responses. For instance, both PDGFRα and PDGFRβ autophosphorylate and thereby create a docking sites for SH2 domain-containing proteins such as

PDGF-mediated

As mentioned above, similarities between certain PDGF and PDGFR knock out mice indicate that PDGF-dependent activation of PDGFRs is essential for normal development. Eliminating either PDGFRB, or PDGF-B reduces the number of pericytes and vascular smooth muscle cells, and thereby compromises the integrity and/or functionality of the vasculature in multiple organs, including the brain, heart, kidney, skin and eye (Soriano, 1994, Lindahl et al., 1997, Lindahl et al., 1998, Leveen et al., 1994). A

Therapeutic options

Existing ligand-directed therapies include aptamers and antibodies that selectively recognize a desired PDGF isoform (Lewandowski et al., 2016a, Heldin, 2014, Heldin, 2013). They are typically highly selective, i.e. do not target growth factors outside of the PDGF family, and distinguish amongst the PDGF isoforms. The disadvantage of targeting a specific PDGF isoform is that it may not prevent activation of PDGFRs because multiple isoforms activate a given PDGFR (Table 1). For example, it is

Conclusions

We currently appreciate that the PDGF/PDGFR family makes multiple contributions to physiology in distinct anatomical locations, and that the two PDGFRs have distinct functions. Furthermore, while ligand-driven activation is the major mode of de-repressing the kinase activity of PDGFRs, there are additional mechanisms. Activated PDGFRs trigger signaling events that direct a spectrum of cellular responses that underlie both physiology and pathology. Two types of advances will set the stage for a

Acknowledgements

This review and the corresponding Gene Wiki article are written as part of the Gene Wiki Review series–a series resulting from a collaboration between the journal GENE and the Gene Wiki Initiative. The Gene Wiki Initiative is supported by National Institutes of Health (GM089820). Additional support for Gene Wiki Reviews is provided by Elsevier, the publisher of GENE.

The corresponding Gene Wiki entry for this review can be found here:

https://en.wikipedia.org/wiki/PDGFRA

//en.wikipedia.org/wiki/PDGFRB

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Gene wiki reviewPDGFs and their receptors

Highlights

Abstract

Section snippets

The PDGF family and their relationships

PDGF-mediated

PDGF-mediated

Therapeutic options

Conclusions

Acknowledgements

Cytokine Growth Factor Rev.

Exp. Eye Res.

Cytokine Growth Factor Rev.

Curr. Opin. Genet. Dev.

Mol. Cell

Cell

Exp. Eye Res.

Dev. Cell

Dev. Cell

Ophthalmology

Am. J. Pathol.

Am. J. Pathol.

Prog. Retin. Eye Res.

Am. J. Pathol.

J. Biol. Chem.

Exp. Neurol.

Blood

Cytokine Growth Factor Rev.

EBioMedicine

Biophys. J.

Imatinib enhances functional outcome after spinal cord injury

PLoS One

Imatinib ameliorates neuroinflammation in a rat model of multiple sclerosis by enhancing blood-brain barrier integrity and by modulating the peripheral immune response

PLoS One

Role of platelet-derived growth factors in physiology and medicine

Genes Dev.

Purification of human platelet-derived growth factor

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

Pericytes regulate the blood-brain barrier

Nature

Anti-PDGFR-alpha antibodies measured by non-bioactivity assays are not specific for systemic sclerosis

Ann. Rheum. Dis.

Vascular endothelial growth factor can signal through platelet-derived growth factor receptors

J. Cell Biol.

Multiplex bead analysis of vitreous humor of patients with vitreoretinal disorders

Invest. Ophthalmol. Vis. Sci.

Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis

N. Engl. J. Med.

Vitreous vascular endothelial growth factor concentrations in proliferative diabetic retinopathy versus proliferative vitreoretinopathy

Ophthalmic Res.

Lack of evidence of stimulatory autoantibodies to platelet-derived growth factor receptor in patients with systemic sclerosis

Arthritis Rheum.

Balance of vascular endothelial growth factor and pigment epithelial growth factor prior to development of proliferative vitreoretinopathy

Ophthalmic Res.

A specific requirement for PDGF-C in palate formation and PDGFR-alpha signaling

Nat. Genet.

Compensatory mutants of the bovine papillomavirus E5 protein and the platelet-derived growth factor beta receptor reveal a complex direct transmembrane interaction

J. Virol.

The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism

Nat. Rev. Genet.

Amplification and/or overexpression of platelet-derived growth factor receptors and epidermal growth factor receptor in human glial tumors

Cancer Res.

The bovine papillomavirus type 1 E5 transforming protein specifically binds and activates the beta-type receptor for the platelet-derived growth factor but not other related tyrosine kinase-containing receptors to induce cellular transformation

J. Virol.

Fusion of PDGF receptor b to a novel ets-like gene, tel, in chronic myelomoncytic leukemia with t(5;12) chromosomal translocation

Cell

Gene wiki review
PDGFs and their receptors